In vitro cytotoxicity of montelukast in HAPI and SH-SY5Y cells.

Montelukast is a cysteinyl leukotriene (CysLT) receptor antagonist with efficacy against a variety of diseases, including asthma and inflammation-related conditions. However, various neuropsychiatric events (NEs) suspected to be related to montelukast have been reported recently, with limited understanding on their association and underlying mechanisms. This study aimed to investigate whether montelukast can induce neuroinflammation and neurotoxicity in microglial HAPI cells and neural SH-SY5Y cells. The present study also compared the effects of montelukast with a 5-lipoxygenase inhibitor (zileuton) and a cyclooxygenase-2 inhibitor (celecoxib) to better understand modulation of related pathways. HAPI or SH-SY5Y cells were treated with the indicated drugs (3.125 µM-100 µM) for 24 h to investigate drug-induced neuroinflammation and neurotoxicity. Montelukast induced cytotoxicity in HAPI cells (50-100 µM), accompanied with caspase-3/7 activation, prostaglandin E2 (PGE2) release, and reactive oxygen species (ROS) production. Whilst both montelukast and zileuton down-regulated CysLT release in HAPI cells, zileuton did not significantly affect cell viability or inflammatory and oxidative factors. Celecoxib decreased HAPI cell viability (6.25-100 µM), accompanied with increasing caspase-3/7 activation and ROS production, but in contrast to montelukast increased CysLT release and decreased PGE2 production. Similar to observations in HAPI cells, both montelukast and celecoxib (50-100 µM) but not zileuton produced toxicity in SH-SY5Y neuroblastoma cells. Similarly, CM from HAPI cells treated with either montelukast or zileuton produced toxicity in SH-SY5Y cells. The results of the current study show the capability of montelukast to directly induce toxicity and inflammation in HAPI cells, possibly through the involvement of PGE2 and ROS, and toxicity in undifferentiated SH-SY5Y neuroblastoma cells. The current study highlights the importance of consideration between benefit and risk of montelukast usage and provides references for future investigation on decreasing montelukast-related NEs.

Pulmonary atresia in prenatal life.

Seven cases of pulmonary atresia with intact ventricular septum were detected in prenatal life. In two of these cases, there was a small hypertrophied right ventricle of the type commonly seen postnatally. In the remaining five cases, the right atrium and right ventricle were grossly dilated to a degree that caused lung compression. The resulting impairment of lung development appeared to be an important factor contributing to death in all five cases. Decompression of the right ventricle by intrauterine surgery to allow normal lung development in the last weeks of pregnancy may be the only way of changing this outcome.

Transcatheter embolization in the treatment of coronary artery fistulas.

Seven patients with a coronary artery fistula underwent percutaneous transcatheter embolization (five were male and two female; the age range was 2 to 67 years [median 17]). Three patients were symptomatic. The left to right shunt ranged from 1.6 to 2.6:1. In six patients, the fistula was an isolated congenital anomaly; in one, it was acquired. The fistula arose from branches of the left (n = 5) and right (n = 2) coronary arteries and drained to the right ventricle (n = 2), right atrium (n = 2), coronary sinus (n = 1), pulmonary artery (n = 1) and a bronchial artery (n = 1). Different embolization techniques were used to occlude eight feeding arteries. The embolization materials included a detachable balloon (n = 3), coaxial embolization with platinum microcoils (n = 3), a combination of detachable balloon and microcoil (n = 1) and standard steel coils (n = 1). Satisfactory occlusion was achieved in six patients. In one case, the valve of the detachable balloon was damaged, resulting in early balloon deflation and a residual fistula. There were no associated complications in any patient. Follow-up investigation by Doppler ultrasound or coronary angiography 4 months to 4 years later showed that permanent occlusion was achieved in all six patients in whom embolization was initially successful. Transcatheter embolization should be considered the treatment of choice for coronary artery fistulas.

Influence of anatomic correction for transposition of the great arteries on myocardial perfusion: radionuclide imaging with technetium-99m 2-methoxy isobutyl isonitrile.

OBJECTIVES: We sought to determine the incidence of late perfusion defects attributable to coronary artery mobilization in patients undergoing anatomic correction for complete transposition of the great arteries. BACKGROUND: Anatomic correction (arterial switch procedure) is currently the surgical treatment of choice for complete transposition. From its conception, there has been concern about the impact on myocardial perfusion of the coronary artery mobilization and reimplantation involved in the correction. Previous studies have demonstrated myocardial perfusion defects in patients after correction, although a causal relation between coronary mobilization, and perfusion abnormality has not been established. METHODS: In a case-comparison study designed to test this hypothesis, 29 children underwent imaging with technetium-99m 2-methoxy isobutyl isonitrile (technetium-99m mibi). Ten had undergone anatomic correction (arterial switch group; interval from operation 6.9 +/- 1.42 years [range 4.9 to 9.1]); 9 had required noncoronary open heart surgery for other cardiac lesions (post-bypass group; interval from operation 5.6 +/- 3.6 years [range 1.0 to 13.25]); and 10 had had no surgical procedure (control group). The latter group comprised children with atrial or ventricular septal defects who required a radionuclide study for shunt calculation. Planar studies were performed in all 29 children, and additional tomographic acquisition was achieved in 25. To assess reversibility of perfusion defects both an exercise and a rest planar study were performed in the arterial switch group. RESULTS: Perfusion abnormalities were observed in seven of the nine children in the postbypass group and in all 10 children in the arterial switch group. The frequency of perfusion defects in these two groups was similar, with at least 25% of the tomographic segments reported being abnormal. The control group had significantly fewer defects than the other two groups (p = 0.02), with only 8% of the tomographic segments judged to be abnormal. In all except one patient in the arterial switch group, the segments reported as abnormal on the planar exercise study were either abnormal or equivocal on the rest study, indicating a fixed abnormality. CONCLUSIONS: Although the precise etiology of these perfusion abnormalities cannot be defined from this study, these data suggest that their origin is related more to the insult of open heart surgery itself than to the coronary manipulation involved in the arterial switch procedure. The functional importance requires further study.

A quantitative evaluation of aortic regurgitation after anatomic correction of transposition of the great arteries.

Twenty patients who had undergone anatomic correction of transposition of the great arteries were assessed by Doppler echocardiography or cardiac catheterization, or both, to identify the presence of aortic regurgitation. The severity of aortic regurgitation was evaluated by radionuclide angiographic measurement of the stroke volume index a mean of 47.1 months postoperatively. The stroke volume index was defined as the ratio of the stroke counts between the left and right ventricles. A value greater than 1.8 was considered to indicate significant left ventricular volume overload. Eight patients (40%) were shown to have various degrees of aortic regurgitation by Doppler echocardiography or cardiac catheterization, or both. The mean (+/- SD) stroke volume index was 1.03 +/- 0.15 in these patients and 1.01 +/- 0.21 in the 12 patients without aortic regurgitation (p = NS). The stroke volume index was not above the normal range in any patient, indicating that the degree of aortic regurgitation present was trivial. This medium-term study indicates that trivial or mild aortic regurgitation is a frequent finding after anatomic correction of transposition of the great arteries. However, it rarely results in an audible cardiac murmur or significant left ventricular volume overload. Long-term evaluation is required to determine its importance.

Direct effect of acebutolol on force generation in immature and adult myocardium.

The effect of acebutolol on active isometric force generation has been studied in isolated papillary muscle preparations from adult cats and kittens less than 24 h old. Statistically significant reduction in active force occurred at a concentration of 0.27 mmol-litre-1 in the adult preparations and at 1.34 mmol-litre-1 in the infant ones. At 2.86 mmol-litre-1 active force had fallen to 43.4%+/-2.2 (SEM) of the control value in the adults and to 52.4%+/-3.3(SEM) in the infants. These results suggest that the infant myocardium is no more sensitive to the negative inotropic effect of acebutolol than is the adult myocardium.

Postnatal maturation of noradrenaline uptake and release in cat papillary muscles.

Catecholamine uptake and release have been studied in isolated right ventricular papillary muscles from kittens aged less than 24 hours, 16 to 18 days and 28 to 32 days. Under the age of 24 h catecholamine uptake (uptake I) does not appear to be functioning and at this age there is a significantly lower response to tyramine. These results suggest that myocardial sympathetic innervation continues to mature, in the cat, after birth.

Postnatal ultrastructural changes in the cat myocardium: a morphometric study.

In order to understand more clearly the basis for our previously observed postnatal age related changes in the mechanical performance of the cat myocardium we have carried out a quantitative ultrastructural analysis of right ventricular papillary muscles obtained from adult cats (1.8 to 2.3 kg), infant cats (16 days of age), and neonatal kittens (less than 72 hours old). Volume fractions were calculated for myofibrils, sarcoplasm, mitochondria, lipid, sarcoplasmic reticulum (SR), golgi, and nuclei. The myofibril content of neonatal fibres was significantly less than that of the infant or adult groups (P less than 0.05 and 0.005 respectively). In addition the infant fibres contained a smaller volume of myofibrils than the adult ones (P less than 0.001). The mitochondrial content of the neonatal fibres was also significantly less than that of either the infants' (P less than 0.005) or adults' (P less than 0.001). These data provide an anatomical basis for the progressive age related increase in mechanical performance of the cat myocardium, in postnatal life.

Seasonal and sexual variations in the responsiveness of rabbit hearts to prolactin.

Rabbit hearts perfused by the Langendorff technique were studied. The addition of ovine prolactin (NIH-P-S-10) to the perfusate in a concentration of 50 ng/ml produced rapid increases in both the amplitude and rate of contraction in 33 adult male hearts studied in winter. Prepubertal male animals showed no response, and only 1 out of 12 adult females responded. Pretreatment for 10 days with 2.5 mg/day testosterone propionate led to minimal inotropic but not chronotropic responses in 2 out of 4 prepubertal males and 2 out of 4 adult females to prolactin. Clear responses to prolactin were seen in 5 adult males pretreated with reserpine. Propanolol consistently reversed both the inotropic and chronotropic actions of prolactin. The original experiments were performed in January and February. When tested in May, adult males failed to respond to prolactin and this situation, persisted until October when responsiveness again appeared. The same prolactin preparation and procedures were used throughout indicating that the changes must have been due to seasonal variations in the cardiac responsiveness to the hormone.

Erythrocyte membrane fatty acid composition as a marker of dietary compliance in hyperlipidaemic subjects.

Dietary intervention is the first treatment step in management of hyperlipidaemia, but there are few objective criteria of compliance. Whether intensive dietary intervention would produce a detectable change in erythrocyte membrane fatty acid composition which could be used as a marker of compliance was examined in 31 new hyperlipidaemic patients. Over a 6 month period, body mass index fell from 29.0 to 26.9 kg/m2 (P < 0.001) and total cholesterol by 19% from 8.16 to 6.58 mmol/l (P < 0.001). The energy derived from fat was reduced from 38.5% to 29.6% (P < 0.001), and the ratio of dietary polyunsaturated to saturated (P:S) fatty acids in the diet increased from 0.45 to 0.66 (P < 0.01). Small but significant changes were recorded in several red cell membrane fatty acids, and the P:S ratio increased from 0.91 to 1.13 (P < 0.001). It would appear, therefore, that red cell membrane changes parallel dietary changes and hence are a potential marker for compliance with dietary changes.

Balloon angioplasty for the treatment of native coarctation: results of Valvuloplasty and Angioplasty of Congenital Anomalies Registry.

Data on dilation of 141 native coarctation procedures in 140 patients between 3 days and 29 years of age were submitted to the Valvuloplasty and Angioplasty of Congenital Anomalies (VACA) Registry. Fifteen patients were less than 4 weeks old, 15 between 1 month and 12 months old and 110 patients over 1 year old. The immediate results confirmed that native coarctations could be effectively dilated in both infants and older children. The data do not support any conclusions concerning balloon size relative to results or complications. There were 24 complications (17%) reported with 1 death after 3 days and after intervening surgery in an infant with associated persistent ductus arteriosus. There were 2 early and 6 late "aneurysms" reported after the coarctation dilations with insufficient immediate and no long-term information about the significance of these. The VACA Registry data suggest that dilation of native coarctations can be performed effectively and relatively safely but do not answer whether this procedure should be performed.

Effect of introducing balloon dilation of native aortic coarctation on overall outcome in infants and children.

The outcome of 40 consecutive newborns and children with normal cardiac connections presenting with unoperated (i.e., no previous surgical or balloon dilation treatment) aortic coarctation since the introduction of balloon dilation as a treatment option (group A) was compared retrospectively with that of a similar cohort of 38 patients (group B) presenting in the period immediately before the introduction of balloon dilation. Group A consisted of 18 newborns (< 30 days) and 22 children and Group B consisted of 20 newborns and 18 children. In group A, 30 patients had balloon dilation but 10 underwent surgery because of parental preference, unfavorable anatomy or for logistic reasons. Group B had conventional surgical repair by various methods. All patients were followed up clinically by Doppler echocardiography and, when possible, by magnetic resonance imaging. Repeat cardiac catheterization was only performed in those with suspected recoarctation. Survival and freedom from reintervention were investigated using Kaplan-Meier analysis. Patients of all ages in group A and those who had balloon dilation were at higher risk for reintervention (25 and 30%, respectively, at 1 year) than those in group B or those who had surgery (20 and 18%, respectively, at 1 year). Mortality was not significantly different between groups A and B, but there were 2 neonatal deaths directly attributable to the dilation procedure. Two patients developed aneurysms after dilation. Balloon dilation is an effective treatment for unoperated coarctation, but the recoarctation rate appears to be higher than for surgery.

Radionuclide measurement of right ventricular function in atrial septal defect, ventricular septal defect and complete transposition of the great arteries.

Right ventricular (RV) function was assessed in 80 patients with congenital heart disease by first-pass and gated equilibrium radionuclide angiography. In 30 patients with a ventricular septal defect (VSD) the mean RV ejection fraction (+/- standard deviation) was 64 +/- 7%. In 30 patients with a secundum atrial septal defect it was 61 +/- 9% and in 20 patients with surgically corrected complete transposition of the great arteries it was 49 +/- 13%. These values are in close agreement with values established with cineangiography for similar groups of patients. The mean ejection fraction in the group with transposition of the great arteries was significantly less than in the group with VSD (p less than 0.001). Phase analysis of the equilibrium studies showed that there was delayed RV contraction in many patients in the absence of conduction abnormalities. This delay was significantly greater in patients with atrial septal defect than in those with VSD (p less than 0.05). There was a strong correlation between size of left-to-right shunt and phase delay in patients with VSD (r = -0.72). Thus, first-pass gated radionuclide angiography provides a valid measurement of RV ejection fraction, and delayed RV contraction on phase analysis may be a sensitive index of early RV dysfunction.

Familial recurrence of congenital heart disease in a prospective series of mothers referred for fetal echocardiography.

Fetal echocardiography can ascertain, at an early stage in pregnancy, recurrences of congenital heart disease (CHD) in mothers with a family history of CHD. In 1,021 mothers referred for this reason, 20 recurrences were found; 17 occurred when there had been 1 previously affected child, and 3 when there had been 2 previously affected children. No recurrences were found in the 41 cases in which a parent had CHD. The overall recurrence rate was 1 in 52 with a previously affected child and 1 in 10 with 2 previously affected children. However, certain forms of CHD recurred much more frequently than others. Aortic valve atresia was associated with a recurrence rate of 1 in 28, coarctation of the aorta at a rate of 1 in 15, complex CHD at a rate of 1 in 11 and truncus arteriosus at 1 in 13. These findings are inconsistent with previous family studies; this may be due to more complete ascertainment, particularly of major lesions, possibly overlooked by postnatal family studies because of fetal loss. Alternatively, the availability of prenatal diagnosis may be producing an increase in family size after major CHD. The results support current doubts on the polygenic theory of inheritance for all forms of CHD.

Determinants of hemodynamic results of balloon dilation of aortic recoarctation.

Between October 1982 and May 1990, balloon dilation of aortic recoarctation was attempted in 27 patients. In 1 case dilation was not performed owing to suspected aortic perforation. The remaining 26 patients had 30 procedures. The age at the first dilation ranged between 2.6 months and 18.3 years. After dilation, systolic gradient decreased from 49 +/- 17 mm Hg to 20 +/- 17 mm Hg (p less than 0.001). A reduction of gradient to less than or equal to 20 mm Hg occurred after the first dilation in 17 of 26 (65%) patients. Residual gradients between 25 and 80 mm Hg were present in the remaining 9 patients. During follow-up of 2 months to 6.7 years, 5 of 17 patients with a good initial result developed further recoarctation (2 had successful redilation, 2 had reoperation, and 1 is awaiting repeat dilation). Of 9 patients with gradients greater than 20 mm Hg after the first dilation, 1 had successful redilation and 3 had reoperation. The remaining 5 patients are being managed conservatively. 2 patients developed aneurysms after dilation (1 immediately and the other at 2 months). In all, 15 patients (58%) had a good, and 11 (42%) a poor late hemodynamic result. Aortic diameters at different levels of the aortic arch and at the reconstructed isthmus (normalized to the aorta at the level of the diaphragm) were significantly higher in the group with a good late result than in that with a poor one. Balloon/aortic diameter ratio at diaphragm level also had a significant influence on the late results.

Use of interlocking detachable coils in embolization of coronary arteriovenous fistulas.

Thirteen patients underwent transcatheter closure of coronary artery fistulas using interlocking detachable coils alone or combined with fibered coils. Complete occlusion was achieved in 92% of patients; although inadvertent embolization of coils occurred in 23% of patients, all these coils were easily retrieved using snares.

The univentricular atrioventricular connection: getting to the root of a thorny problem.

Most hearts described as "single ventricle" or "univentricular heart" possess 2 ventricular chambers, even though 1 is usually described as an "outlet chamber." This stems from the wide acceptance that the criterion of a single ventricle is the presence of a double-inlet atrioventricular (AV) connection. In recent years, using this criterion, an attempt was made to show how hearts with double-inlet right ventricle or "classic tricuspid atresia" were (in terms of ventricular morphology) just as univentricular as "single ventricle with outlet chamber." This attempt brought still further confusion to an already contentious topic. The root of the problem clearly is the injudicious use of the adjective "single" or "univentricular." Conventionally it is used to describe the ventricular mass. In most hearts with double-inlet connection it is not the ventricles that are univentricular; it is the AV connection. The concept of a univentricular AV connection, then, appropriately groups hearts with double-inlet along with those having absence of 1 AV connection. It distinguishes this entire group from those other hearts with biventricular AV connections (each atrium connected to its own ventricle). The term "univentricular AV connection" is thus a collective one for all those hearts in which the atria connect to only 1 ventricle. Confusion will be completely removed if individual hearts are described for what they are in terms of AV connection and ventricular morphology (for example, double-inlet left ventricle with rudimentary right ventricle rather than single ventricle with outlet chamber).

Growth of the right ventricle after successful transcatheter pulmonary valvotomy in neonates and infants with pulmonary atresia and intact ventricular septum.

OBJECTIVES: Since 1990, transcatheter pulmonary valvotomy has become an alternative to surgical valvotomy in the management of neonates and infants with pulmonary atresia and intact ventricular septum. We sought to determine whether right ventricular growth after transcatheter pulmonary valvotomy is commensurate with body growth. METHODS: Laser or radiofrequency-assisted balloon valvotomy was attempted in 12 neonates and infants with pulmonary atresia and intact ventricular septum. Tricuspid and mitral valve dimensions were measured retrospectively on the cross-sectional echocardiograms performed before the procedure and during follow-up. Z-values were used to standardize tricuspid valve dimensions with body size. RESULTS: The atretic pulmonary valve was successfully perforated and dilated in nine of 12 patients. Five of these nine patients required additional transcatheter or surgical procedures to augment the pulmonary blood flow. Of six survivors, five are regularly followed up with a median follow-up of 60 months (range 37 to 68 months). All five have two-ventricle circulation, two of the five patients requiring surgical enlargement of the right ventricular outflow tract with or without closure of the atrial septal defect. Echocardiographic tricuspid valve dimensions and Z-values before transcatheter valvotomy tended to be smaller in the patients who died than in the survivors. In the survivors, the absolute tricuspid valve dimensions increased after valvotomy but the Z-values tended to decrease or stayed constant. CONCLUSIONS: Transcatheter valvotomy is a good alternative to surgical valvotomy in patients with pulmonary atresia and intact ventricular septum. Two-ventricle circulation can be achieved despite subnormal right ventricular growth.

Aortic coarctation in the first three months of life. An anatomopathological study with respect to treatment.

Operation for coarctation in infancy is a lifesaving procedure, but it still carries a high mortality and is followed frequently by recurrence of stenosis. This is especially true when the procedure is performed in the first 3 months of life. To determine a correlation, if any, between anatomy of coarctation and surgical procedures, we have studied a series of 42 autopsy specimens from patients younger than 3 months who had aortic coarctation. We found that concepts of coarctation based solely on a discrete lesion or isthmic hypoplasia were simplistic. The anatomy was much more complex, the findings being relevant to surgical techniques currently in use (resection and end-to-end anastomosis, subclavian flap aortoplasty). Of equal significance in the cases we studied to the presence of a shelf of ductal tissue within the aortic lumen or hypoplasia of a segment of the arch was the finding of "waist" lesions. In these cases the wall of the aorta was constricted to form the obstruction. Such "waists" coexisted with discrete shelves or with shelves and isthmic narrowing. While we recognize the danger of extrapolating from autopsy findings to predict clinical results, our observations suggest that surgical procedures might best be tailored to the precise anatomy present. It seemed that in may cases a subclavian flap procedure offered the best chance of success. Cases with anatomy suitable for resection and end-to-end anastomosis were less frequent. Percutaneous angioplasty seemed at best to offer only palliative options in limited cases.

Superoxide dismutase improves posttraumatic cortical blood flow in rats.

Oxygen free radicals, such as the superoxide anion, are known to mediate damage to the cerebral microcirculation following traumatic brain injury. The purpose of this study was to determine if superoxide dismutase (SOD), a scavenger of superoxide anion, could alter posttraumatic cortical blood flow. Following barbiturate anesthesia, rats were surgically prepared for moderate fluid percussion brain injury. Cortical blood flow contralateral to the site of injury was measured using laser-Doppler flowmetry. Laser-Doppler flowmetry assesses flow by measuring cell volume and velocity, which are multiplied electronically to give flow. Starting 10 min before injury, animals received either superoxide dismutase (24,000 U/kg bolus, followed by continuous infusion of 1600 U/kg/min) or an equal volume of saline. Blood pressure, heart rate, and cortical blood flow were measured up to 1 h posttrauma. Rats receiving superoxide dismutase had significantly higher cortical blood flow posttrauma (F = 6.91, p < 0.02). One hour posttrauma, the blood flow in SOD-treated rats was 89 +/- 8% of preinjury baseline, whereas this value was only 66 +/- 6% of control in saline-treated rats. SOD caused not only greater blood velocity but also less reduction in cortical blood volume after injury. There were no significant differences between the groups with respect to blood pressure or heart rate. This study further supports the role of oxygen radical-mediated cerebrovascular dysfunction following traumatic brain injury and is the first to show the beneficial effect of SOD on cortical blood flow following fluid percussion brain injury.