Cardiac abnormalities 15 years and more after adriamycin therapy in 229 childhood survivors of a solid tumour at the Institut Gustave Roussy.

The purpose of this paper was to determine the cardiac status in children 15 years or more after adriamycin therapy for a solid tumour. Of the 447 pts, 229 pts were fully studied and 218 were not. The following cardiac evaluations were proposed to all the 447 consecutive patients (pts): (1) cardiac Doppler US by one of two expert cardiologists; (2) cardiac rhythm and conduction abnormalities including 24-hour holter ECG; (3) (131)l-mlBG myocardial scintigraphy; (4) serum brain natriuretic peptide levels at rest; (5) an exercise test with VO(2) max measurement. The radiation doses delivered to 6 points in the heart were estimated for all patients who had received radiotherapy. Congestive heart failure was diagnosed in 24 of 229 (10%) evaluated pts, with a median interval of 15 years (0.3-24 years) from the first symptom after adriamycin treatment. Among the 205 remaining pts, 13 asymptomatic pts (6%) had severe (n=4) (FS<20%) or marked (n=9) (20< or =FS<25%) systolic dysfunction. In the 192 others, the median meridional end-systolic wall stress was 91 (53-135) and it exceeded 100 g cm(-2) in 52 pts. Using a Cox model, only the cumulative dose of adriamycin and the average radiation dose to the heart, were identified as risk factors for a pathological cardiac status. In conclusion, the risk of cardiac failure or severe abnormalities increases with adriamycin treatment, radiotherapy and time since treatment, even after a follow-up of 15 years or more. In our series, after an average follow-up of 18 years, 39% of the children had a severe cardiac dysfunction or major ventricular overload conditions. The risk increases with the dose of adriamycin and radiation received to the heart, without evidence for threshold.

Pathogenesis of twin-twin transfusion syndrome: the renin-angiotensin system hypothesis.

In spite of active perinatal management, twin-twin transfusion syndrome (TTTS) remains a severe disease with a high risk of neonatal mortality and morbidity. TTTS initially results from an unbalanced blood flow from a donor to a recipient twin. However, its pathogenesis remains unclear, although cardiovascular disturbances and regulation of fetal volemia and diuresis seem central in this syndrome. Previously, we demonstrated that the renin-angiotensin system (RAS) was up-regulated in donor twins as a consequence of hypovolemia, and down-regulated in recipients. This was the first evidence of the implication of the RAS in TTTS. We hypothesize that the RAS plays a key role in the pathogenesis of TTTS. In the donor, RAS up-regulation aggravates oligohydramnios and may increase arterial resistance, which could contribute to placental dysfunction leading to intrauterine growth restriction. In the recipient, paradoxical RAS activation, due to transfer of effectors such as angiotensin II through placental shunts, could explain fetal vascular disturbances and cardiomyopathy. According to our hypothesis, TTTS would appear similar to the classical model of hypertension referred to as '2 kidneys-1 clip' with a donor twin, comparable to the clipped kidney, intoxicating its cotwin, comparable to the normal kidney.

Fetal and neonatal hypertension in twin-twin transfusion syndrome: a case report.

We report a case of fetal systemic hypertension. This occurred in an ex-donor twin soon after coagulation of chorionic vessels and amniodrainage performed for severe twin-twin transfusion syndrome during the 2nd trimester of pregnancy. Systemic hypertension was suspected because of a high systolic velocity through the tricuspid valve, and Bernoulli's equation was used to estimate the right intraventricular pressure. As both pulmonary arteries and ductus arteriosus were normal, the pressure in the aorta was considered to be equal to that in the right ventricle (60 mm Hg). Fetal systemic hypertension could have happened either because of a dramatic increase in placental resistances in the territory of the ex-donor twin or by reversal of the fetofetal transfusion pathological process.

Efficiency of metabolic screening in childhood cardiomyopathies.

AIM: To estimate the efficiency of metabolic screening in children's cardiomyopathy. METHODS AND RESULTS: Blood glucose, lactate, pyruvate and ketone body, and carnitine levels were measured in 58 children referred with a cardiomyopathy of unknown origin. Organic acids, amino acids, oxidation of [1-14C] fatty acids to CO2 and dehydrogenation of [9,10(-3)H] fatty acids by lymphocytes were measured. Mitochondrial respiratory chain complex activity was measured in skeletal muscle and in endomyocardial biopsies. Acid a-glucosidase activity was measured in infants with hypertrophic cardio-myopathy. The prevalence of metabolic disorders was 22.4% (13/58-CL95%; 11.4-33.3%): four infants had a storage disease (Pompe's disease (3), Hurler's disease (1); two patients had a fatty acid beta-oxidation defect (systemic carnitine deficiency (1) and very-long chain acyl-CoA dehydrogenase deficiency (1)); respiratory enzyme deficiency was diagnosed in seven patients. This defect was confined to the myocardium in six. In the remaining 45 patients, metabolic screening was unrevealing. CONCLUSION: Metabolic screening should be performed in all children with cardiomyopathy as the prevalence of metabolic disorders is high in this population. This may help to define therapeutic strategy and to improve genetic counselling.

Endomyocardial biopsies for early detection of mitochondrial disorders in hypertrophic cardiomyopathies.

Considering the high proportion of unexplained hypertrophic cardiomyopathies on the one hand and the occurrence of cardiomyopathies in several mitochondrial disorders on the other, we hypothesized that isolated hypertrophic cardiomyopathies in infancy could occasionally be the result of defects of oxidative phosphorylation. By means of a scaled-down technique, we were able to investigate oxidative phosphorylation on minute amounts of endomyocardial tissue (1 mg) in three patients with concentric hypertrophic cardiomyopathy (shortening fraction in diameter, 18% to 27%; normal mean +/- 1 SD, 33 +/- 3%) and in control subjects. Although the absolute respiratory chain enzyme activities in the endomyocardial biopsy specimens of the patients were within the low normal range, the determination of the activity ratios allowed us to ascribe hypertrophic cardiomyopathies to respiratory chain enzyme abnormalities in all three cases (complex I, two cases; multiple enzyme deficiency, one case). The respiratory chain enzyme activity ratios, which are normally constant irrespective of the tissue tested, were markedly abnormal in all three patients (cytochrome c oxidase/reduced nicotinamide-adenine dinucleotide cytochrome c reductase, 4.6 to 10.4; normal mean +/- 1 SD, 2.9 +/- 0.5). We conclude that mitochondrial disorders should be regarded as potential causes of hypertrophic cardiomyopathy in early infancy. Because cardiac catheterization is routinely performed for hemodynamic investigation of cardiomyopathies, we suggest that endomyocardial biopsies be considered as a tool for early detection of mitochondrial cardiomyopathies, especially in hypertrophic forms of the disease.

Investigation of respiratory chain activity in human heart.

Although disorders of oxidative phosphorylation have long been regarded as neuromuscular diseases only, they can actually give rise to any symptom specifically affecting any organ or tissue, particularly in childhood. The early diagnosis of such a condition may thus require the specific assessment of the mitochondrial function in the organ or tissue shown to be clinically involved. A method is presented allowing such an early detection of respiratory chain defects in human heart. Respiratory chain enzyme studies were carried out using endomyocardial biopsies, less than 2 mg fresh weight. Enzyme activities measured in the endomyocardial biopsies were compared with those obtained using other sampling methods (surgical and postmortem microsamples). A comparison of the respiratory chain enzyme activities in heart and other human tissues is also presented. It was found that (i) the activities of respiratory chain complexes in human heart were similar with any sampling method; (ii) these activities were high compared to other human tissues, allowing the use of heart microsamples for enzyme measurements; (iii) the activity ratios between complexes of the respiratory chain were similar in heart and other human tissues or cells as well, allowing us to confidently characterize potential mitochondrial defects and to compare their expression in different tissues or cells. The value of such investigations on endomyocardial biopsies is illustrated in the case of two patients affected with mitochondrial cardiomyopathy and is discussed in regard to the tissue-specific nature of mitochondrial diseases.

Heart transplantation in children: mid-term results and quality of life.

From 1987 to 1991, heart transplantation was undertaken in 49 infants and children with either end-stage cardiomyopathies (28 patients) or severe congenital heart disease (21 patients including 16 having already been surgically but unsuccessfully treated). Their age ranged from 13 days to 15 years (mean = 4.5 +/- 4.2 years; median = 2.5 years). There were 12 early and 7 late deaths (overall mortality = 38%), mainly due to graft dysfunction, acute or chronic rejection, and infectious complications, mostly viral. Optimal criteria in selecting both donors and recipients are crucial to reduce early mortality and should never be transgressed despite the critical shortage of organs. The actuarial probability of survival was 64% at 1 year and 57% at 5 years. Our 30 mid-term survivors (62%) were submitted to a close follow up programme which includes endomyocardial biopsies, even in the very young, since non invasive criteria failed to mark every rejection episode. Maintenance therapy was always steroid-free to start with (cyclosporin+azathioprine) but in almost one half of our oldest survivors, it failed to avoid rejection and we had to add low-dose oral steroids for at least several months. Epstein-Barr virus related lymphoproliferations occurred in four patients, two of whom died and two recovered with specific therapy. Renal function was closely monitored: tubular and interstitial lesions were found on renal biopsies and were associated with moderate functional changes. The quality of life of the children who survived heart transplantation was considered as near normal in a little more than one half of the cases but many issues (late coronary disease, drug toxicity, long-term compliance to follow up and therapy) remain significant concerns for the future.

Aortic atresia with normal left ventricle.

A case of single-stage repair of aortic atresia with normal-sized left ventricle and ventricular septal defect in a neonate is reported. The surgical procedure included rerouting of the left ventricular bloodstream to the pulmonary artery through the ventricular septal defect and connection of the pulmonary trunk to the aortic arch. The right ventricular outflow tract was then reconstructed with an extracardiac valved conduit. Three years after the initial operation, replacement of the valved conduit was performed uneventfully. The clinical status of the child is very satisfactory.

Piriprost: a putative leukotriene synthesis inhibitor increases pulmonary blood flow in fetal lambs.

Leukotrienes may control fetal pulmonary vascular tone since infusions of putative leukotriene receptor antagonists markedly increase pulmonary blood flow and decrease pulmonary vascular resistance in fetal lambs. This hypothesis would be strengthened if inhibition of leukotriene synthesis also produced similar hemodynamic changes. We therefore studied the effects of piriprost (U 60257), a putative leukotriene synthesis inhibitor, on thirteen fetal lambs at 137 to 140 days gestation. In preliminary studies in four fetal lambs, doses of U 60257 greater than 20 mg/kg increased pulmonary blood flow. In the nine other fetal lambs, U 60257 (31.7 +/- 4.1 mg/kg) increased pulmonary blood flow by 502% (p less than 0.05) and decreased pulmonary vascular resistance by 87% (p less than 0.05). Pulmonary arterial and left atrial pressures were unchanged. Descending aortic pressure was increased (p less than 0.05) and heart rate was decreased (p less than 0.05). The abilities of both putative leukotriene synthesis inhibitors and leukotriene receptor antagonists to similarly increase fetal pulmonary blood flow and decrease pulmonary vascular resistance are consistent with the hypothesis that leukotrienes play a role in regulating fetal pulmonary vascular tone.

[Problems posed by percutaneous pulmonary valvuloplasty in children]. / Problèmes posés par la valvuloplastie pulmonaire percutanée chez l'enfant.

Percutaneous valvuloplasty with a balloon catheter was attempted in 41 young patients with pulmonary valve stenosis. There were 9 neonates (1 to 7 days), 6 infants (1.5 to 7 months) and 26 children (16 months to 17 years). The attempt failed in 8 cases, either because the balloon could not be inserted due to intravenous progression problems or to quasi-atresia of the orifice, or because serious accidents (air embolism in one patient, perforation of the infundibulum in another) forced us to abandon the procedure before dilatation. Failures mostly occurred in very young children: 7 out of 15 aged less than 1 year, 1 out of 26 older than 1 year. Dilatation was effective in 33 cases. Among 13 patients who had moderate stenosis with infra- or iso-systemic right ventricular systolic pressure (RVP) (mean: 70 +/- 13 mmHg) and modest ventriculo-pulmonary gradient (49 +/- 12 mmHg), there was only 1 failure due to coexistent biventricular myocardiopathy; success was immediate and complete in 8 cases, partial in 4 cases. Among 20 children presenting with tight stenosis with supra-systemic RVP (164 +/- 39 mmHg) and high ventriculo-pulmonary gradient (140 +/- 43 mmHg), there were 5 failures; success was partial in 8 cases, complete and immediate in 7 cases. Accentuation of the infundibular stenosis after dilatation was a frequent cause of failure, as we have shown by calculating the infundibular "reactivity index" on pre- and post-operative angiocardiograms. In such cases one may hope for spontaneous improvement, as was indeed subsequently observed in 2 of our patients.(ABSTRACT TRUNCATED AT 250 WORDS)