Danon disease: case report and detection of new mutation.

Danon disease is an X-linked disorder resulting from mutations in the lysosome-associated membrane protein-2 (LAMP2) gene. We report a male patient with skeletal myopathy, mental retardation, and massive hypertrophic obstructive cardiomyopathy necessitating heart transplantation. Immunohistochemistry of skeletal muscle and leukocytes, western blot analysis of leukocytes and cardiac muscle, flow cytometry, and DNA sequencing were performed. Muscle biopsy revealed autophagic vacuolar myopathy and lack of immunohistochemically detectable LAMP-2. Diagnosis of Danon disease was confirmed by western blot analysis of myocardial tissue and peripheral blood sample of the patient showing deficiency of LAMP-2 in myocardium and leukocytes. Moreover, absence of LAMP-2 in lymphocytes, monocytes and granulocytes was shown by flow cytometric analysis. Genetic analysis of the LAMP2 gene revealed a novel 1-bp deletion at position 179 (c.179delC) at the 3' end of exon 2, resulting in a frameshift with a premature stop codon.

Scintigraphic assessment of pulmonary and whole-body blood flow patterns after surgical intervention in congenital heart disease.

UNLABELLED: Glenn shunt and Fontan procedure, the most widely used surgical procedures in congenital heart anomalies, may be associated with abnormal pulmonary blood flow patterns and the development of pulmonary arteriovenous fistulae. METHODS: This study quantified pulmonary and whole-body blood flow using the microsphere technique by sequential injection of 99mTc microspheres into upper and lower limb veins and performing planar lung imaging in four projections and anterior and posterior whole-body scans in 46 patients with either Glenn shunt or Fontan procedure. The right-to-left shunt volume was estimated by a brain and kidneys-to-lungs ratio and compared with calculations from the whole-body scans. RESULTS: In 31 of 46 patients, the blood from the superior vena cava was drained preferentially into the right lung (75%+/-19%). The inferior venous system was drained equally into both lungs. The right-to-left shunt volume was 24%+/-12% after injection into the superior caval system, 50%+/-18% after injection into the inferior caval system. A subgroup of patients who had undergone a palliative Blalock-Taussig shunt (BTS) before the final surgery showed a perfusion pattern that was not known after pulmonary angiography or contrast echocardiography: 15 of 24 patients with BTS had hypoperfusion of the upper lobe on the side of the BTS after injection into the arm vein and corresponding normal perfusion or hyperperfusion when injected into the foot vein. CONCLUSION: Lung perfusion scintigraphy after tracer application into the superior and inferior caval systems detects more abnormal pulmonary blood flow patterns than contrast echocardiography and is the only procedure able to quantify right-to-left shunt volume individually for the superior and inferior caval systems. Thus, this diagnostic technique should be part of the routine follow-up in children after Glenn shunt or Fontan procedure.

Early failure of the tissue engineered porcine heart valve SYNERGRAFT in pediatric patients.

OBJECTIVES: The first tissue engineered decellularized porcine heart valve, Synergraft (Cryolife Inc., USA) was introduced in Europe as an alternative to conventional biological valves. This is the first report of the rapid failure of these new grafts in a small series. MATERIALS AND METHODS: In 2001, 2 model 500 and 2 model 700 Synergraft valves were implanted in four male children (age 2.5-11 years) in the right ventricular outflow tract as a root. Two patients had a Ross operation and two had a homograft replacement. RESULTS: The cryopreserved Synergraft valves appeared macroscopically unremarkable at implantation. Recovery from surgery was uneventful and good valve function was demonstrated postoperatively. Three children died, two suddenly with severely degenerated Synergraft valves 6 weeks and 1 year after implantation. The third child died on the 7th day due to Synergraft rupture. Subsequently the fourth graft was explanted prophylactically 2 days after implantation. Macroscopically all four grafts showed severe inflammation starting on the outside (day 2 explant) leading to structural failure (day 7 explant) and severe degeneration of the leaflets and wall (6 weeks and 1 year explant). Histology demonstrated severe foreign body type reaction dominated by neutrophil granulocytes and macrophages in the early explants and a lymphocytic reaction at 1 year. In addition significant calcific deposits were demonstrated at all stages. Surprisingly pre-implant samples of the Synergraft revealed incomplete decellularization and calcific deposits. No cell repopulation of the porcine matrix occurred. CONCLUSION: The xenogenic collagen matrix of the Synergraft valve elicits a strong inflammatory response in humans which is non-specific early on and is followed by a lymphocyte response. Structural failure or rapid degeneration of the graft occurred within 1 year. Calcific deposits before implantation and incomplete decellularization may indicate manufacturing problems. The porcine Synergraft treated heart valves should not be implanted at this stage and has been stopped.

Anomalous origin of the left coronary artery: a review of surgical management in 13 patients.

Over the last decades, surgical management of anomalous left coronary artery originating from the pulmonary artery (ALCAPA) has seen a considerable evolution. Between 1965 and 1992, 13 children with age at operation ranging between 2 months and 11 years (mean 23 months) underwent one of 5 different surgical procedures: ligation (n = 3), direct aortic reimplantation (n = 7), subclavian (n = 1) or internal mammary (n = 1) artery anastomosis, or modified aortic implantation (Vigneswaran-procedure, n = 1). There were 3 early and one late deaths resulting in an overall mortality of 30.7%. Mortality was 66.7% in the ligation group, and 20% in the revascularization group (28.6% in the subgroup with direct aortic implantation). The one late death occurred 6 months after ligation. Follow-up ranges between 3 months and 21 years, mean 7.3 years. All but one survivors are in NYHA functional class I. Following operative correction, there was clear improvement in left ventricular performance. Our data give reason to suggest ALCAPA to be more frequent than considered so far. Early surgery is recommended in all patients with ALCAPA, regardless of age or symptomatic status. Reestablishment of a two-coronary system is considered the procedure of choice. All survivors require long-term follow-up controls of early recognition of residual or progressive cardiac problems.

[Immunosuppressive treatment of chronic myocarditis]. / Immunsuppressive Behandlung der chronischen Myocarditis.

6 children aged 9 months to 13 8/12 years developed reduced physical capacity, failure to thrive, dyspnoea on effort and heart failure after viral infection. Bed rest and anticongestive therapy did not reduce the severe heart failure. Immunosuppressive therapy with prednisolone 2 mg/kg/d and azathioprine 2 mg/kg/d was added on the assumption of chronic myocarditis (n = 4) or endocardial fibrosis (n = 2). 3 of the 6 children showed a considerable improvement in heart size, ECG and systolic heart function. Interruption of immunosuppressive therapy due to side effects in one child led to cardiac deterioration, which was reversed by renewed prednisolone therapy. Two patients died of progressive congestive heart failure. Heart transplantation was successfully performed in the now 14 year-old girl who was suffering from terminal dilated cardiomyopathy. Since there is no specific test for selecting patients who are likely to benefit from immunosuppressive therapy we feel this regimen would be justified in hopeless cases of congestive cardiomyopathy who have not responded to conventional therapy with anti-congestive drugs.

[Value of myocardial scintigraphy of coronary anomaly in the differential diagnosis of pediatric cardiomegaly]. / Wertigkeit der Myokardszintigraphie bei Koronaranomalie in der Differentialdiagnose der kindlichen Kardiomegalie.

The differentiation between anomalous origin of the left coronary artery from the pulmonary artery (ALCAPA) and other causes of cardiomegaly and thereby the decision to operate, as opposed to undertaking conservative therapy is often extremely difficult in clinical practice. Electrocardiographically, signs of myocardial infarction can be missed in ALCAPA, other forms of dilative cardiomyopathy (DCMP) often showing similar clinical features. Up to now aortography alone can make a clear-cut distinction between these two entities. In order to determine the diagnostic value of thallium-201 myocardial scintigraphy in ALCAPA, we investigated 18 children, 7 of them with angiographically or autoptically established ALCAPA and 11 patients with DCMP. The coronary artery anomaly was diagnosed on the basis of the typical myocardial perfusion defects in only 3 of the relevant 7 patients. In 9 of the 11 patients with DCMP ALCAPA was excluded by the homogeneous perfusion pattern or small focal reduction in thallium-201 activity in the left ventricular muscle mass. In view of the overall disappointing results of this method in achieving a specific diagnosis in ALCAPA, all patients with DCMP with or without suspected fibroelastosis should undergo invasive diagnosis with aortography.

[Comparison of surgical techniques and various suture materials for correction of aortic isthmus stenosis]. / Vergleich von Operationstechniken und verschiedenem Nahtmaterial zur Korrektur der Aortenisthmusstenose.

UNLABELLED: Clinical examination and Doppler ultrasound were performed in 31 children after repair of coarctation of the aorta. Median postoperative follow-up period was 4.5 years. The aim of our study was a comparison of different operation techniques and suture materials. In 16 infants subclavian flap repair had been performed using polydioxanone absorbable sutures (PDS) in 8 cases and polypropylene (Prolene) sutures in the other 8 cases. Resection and end-to-end repair had been carried out in 8 infants using PDS and in 7 using Prolene sutures. Doppler-echocardiographically derived gradients across the reconstructed aorta were significantly lower in infants operated with the subclavian flap technique (p < 0.05). The length of the arm on the side of the subclavian flap operation was shorter (median 1.2 cm), but there were no signs of ischaemic complications. Using PDS sutures the aortic arch and the aortic isthmus were each morphologically significantly wider in both operation techniques. Noninvasive two-dimensional echocardiography demonstrated good anatomical repair and no anastomotic aneurysm formation after aortic repair using polydioxanone. CONCLUSION: Regarding the doppler-echocardiographically derived gradients in the anastomotic region this intermediate follow-up study reveals better results using the subclavian flap technique; absorbable polydioxanone sutures favour normal growth of the anastomotic site without vascular complications.

[Doppler echocardiographic evaluation of pressure in the pulmonary artery in children with congenital heart defects]. / Dopplerechokardiographische Beurteilung des Drucks in der Arteria pulmonalis bei Kindern mit angeborenen Herzfehlern.

In children with congenital heart disease serial noninvasive assessment of the pulmonary vascular bed is desirable in order to determine the appropriate timing of cardiac catheterization and corrective surgery. To assess the value of pulmonary Doppler echocardiography for the estimation of pulmonary arterial pressure we correlated the rightsided systolic time intervals (preejection period, acceleration period, ejection period) derived from pulmonary artery Doppler traces with catheterization data (systolic, mean and diastolic pulmonary arterial pressure, total and vascular pulmonary resistances). 62 children aged from 1 month to 15 years suffering from congenital heart disease (n = 52), from rheumatic heart disease (n = 4), from cardiomyopathy (n = 5) or from primary pulmonary hypertension (n = 1) were investigated. The major finding was a highly significant correlation between the acceleration period and the systolic pulmonary arterial pressure (r = 0.79; p less than or equal to 0.0001). However the acceleration period could not be used for prediction of pulmonary arterial pressure in children with poor myocardial contractility.

[Hypoplastic left-heart syndrome. Initial intensive care experiences with the Norwood operation in Vienna]. / Hypoplastisches Linksherz-Syndrom. Erste intensivmedizinische Erfahrungen mit der Norwood-Operation in Wien.

Palliative surgery of the hypoplastic left heart syndrome (HLHS), whereby both pulmonary and systemic circulation are restored, was first described by Norwood in 1983. Careful ventilatory and pharmacologic modulation of the ratio of pulmonary to systemic vascular resistance are a crucial part of pre-, peri- and postoperative management. We report our experience in 3 of 7 newborns with HLHS who underwent the Norwood operation. Hemodynamic and respiratory parameters were evaluated retrospectively in these patients and we analysed the influence of diagnostic and therapeutic interventions on the course of disease before and after operation. During prostaglandin therapy two of three patients required mechanical ventilation preoperatively because of pulmonary hyperperfusion. Decreased myocardial contractility, oliguria and increased pulmonary vascular resistance characterized the postoperative course. The management included a careful application of inotropic support when necessary, adaptation of the ventilatory setting in order to modulate pulmonary perfusion and, in addition, institution of peritoneal dialysis. One patient died from staphylococcus aureus and superinfection with respiratory syncytial virus on day 41 after the operation. Maintaining an optimal balance between pulmonary and systemic blood flow is an essential aspect of postoperative management. Serum lactate and central venous oxygen saturation are helpful parameters in monitoring therapeutic measures in these patients. We conclude from our preliminary experience, that the Norwood operation might be an alternative therapeutic approach for newborns with HLHS in whom heart transplantation is not possible.

[Surgical treatment of Bland-White-Garland syndrome in infants and children: experiences with revascularization techniques]. / Zur chirurgischen Behandlung des Bland-White-Garland-Syndroms bei Säuglingen und Kindern: Erfahrungen mit Revaskularisationstechniken.

In comparison with the older technique of ligation of the anomalous coronary artery in Bland-White-Garland syndrome, the various methods of revascularisation have in common the concept of a two coronary artery system. Between 1980 and 1992, 10 children from 6 weeks to 11 years of age (mean 2 years) underwent revascularisation: direct reimplantation of the coronary ostium from the pulmonary artery to the aorta (n = 7), modified implantation with coronary artery elongation (n = 1), bypasses using subclavian artery (n = 1) or the mammary artery (n = 1). Postoperatively, 2 infants died, both following direct reimplantation, resulting in an overall mortality of 20%. There was no late death. All children but one are asymptomatic and do not require medication on follow up for between 3 months and 12 years (mean 5 years) after the procedure. Echocardiography, cardiac catheterisation, and scintigraphy show a significant improvement of left ventricular function and, as a direct consequence, a decrease in preexisting mitral insufficiency. Hence any surgical manipulation at the mitral valve should be avoided at the initial operation. As a principle, the revascularisation procedure should be performed at the earliest possible time to avoid further ischemic myocardial damage. On long-term follow-up, ventricular function and prognosis of the residual low-degree mitral insufficiency remain unclear and require regular control examinations.

[L-carnitine therapy and myocardial function in children treated with chronic hemodialysis]. / L-Carnitintherapie und Myokardfunktion bei chronisch hämodialysierten Kindern.

Six out of 14 chronically hemodialysed children with significantly decreased serum carnitine levels were substituted with L-carnitine (15-30 mg/kg/day-Biocarn) up to normal and above normal carnitine levels. None of these patients were digitalised. During the time of investigation plasma carnitine levels were investigated monthly and, simultaneously, three echocardiographic parameters in M-mode were quantitatively und qualitatively determined: shortening fraction (SF-%), ratio of left ventricular pre-ejection/ejection time (LVPT/LVET) and velocity of circumferential fibre shortening (Vcf). Carnitine substitution produced measurable changes in echocardiographic parameters, and a significant quantitative improvement in left ventricular function and performance: after 6 months of carnitine substitution a 24% improvement was seen, after 18 months a 44% mean improvement. No side effects of carnitine were observed; the compatibility was good. Beside these positive effects all patients reported decreased dialysis-associated spasms and polyneuropathic symptoms and increased somatic ability.

Right ventricular contractility is preserved in patients with cystic fibrosis and pulmonary artery hypertension.

A combined hemodynamic and radionuclide approach was used to evaluate right ventricular contractility in 16 adolescent and adult patients with cystic fibrosis (CF). Nine patients had normal resting pulmonary artery pressure, and seven had resting pulmonary artery hypertension (PH). Right ventricular ejection fraction (RVEF) was observed by radionuclide angiocardiography, and stroke volume index (SVI) by thermodilution techniques. By combination of these measures right ventricular end-diastolic and end-systolic volumes were derived. RVEF was normal in CF patients without PH (58.9 +/- 7.2%) but was reduced in those with PH (45.4 +/- 2.3%). There was a strong inverse linear correlation between RVEF and afterload, as assessed by mean pulmonary artery pressure (r = -0.76), indicating RVEF being afterload-dependent. Right ventricular contractility, however, as assessed by right ventricular end-systolic pressure-volume relations was even higher in CF patients with PH, indicating preserved or even increased contractility in the face of an increased afterload stress. The acceleration time, evaluated by pulsed Doppler echocardiography, was normal in CF patients without PH (117.3 +/- 5.5 msec) and significantly reduced in those with PH (85.1 +/- 6.4 msec). Both RVEF and AT were efficient in estimating pulmonary artery pressure in these patients.

Incidence of thrombotic and bleeding complications during cardiac catheterization in children: comparison of high-dose vs. low-dose heparin protocols.

BACKGROUND: During cardiac catheterization (CC) in children, unfractionated heparin (UFH) is used for primary prophylaxis of thrombotic events (TE). However, the optimal UFH dose to minimize TE and bleeding in children has yet to be established. OBJECTIVES: To (i) objectively assess the incidence of TE and bleeding during pediatric CC using clinical assessment and ultrasound; and (ii) compare a high-dose vs. low-dose UFH protocol for thromboprophylaxis. METHODS: A randomized controlled trial (RCT) comparing high-dose UFH (100 units kg(-1) bolus, followed by 20 units kg h(-1) continuous infusion) vs. low-dose UFH (50 units kg(-1) bolus) during CC. Outcome assessment was by clinical examination and vascular ultrasound, performed by blinded examiners before and within 48 h after CC. Children with no consent for randomization were followed in a cohort receiving standard-of-care UFH (parallel-cohort RCT). RESULTS: A total of 227 children were included; 137 were randomized and 90 followed in the cohort study. The overall incidence of TE was 4.6% and bleeding 6.6%. The RCT was stopped early for futility as there were no differences between the high-dose and the low-dose UFH in TE (5% vs. 3%; risk ratios [RR] 1.5, 95% confidence interval [CI] 0.3; 9) and bleeding (7% vs. 12%, RR 0.6, 95% CI 0.2; 2). There were also no differences when RCT and cohort study populations were combined. CONCLUSIONS: The incidences of TE and bleeding during CC in children were low. There were no differences between the high-dose and the low-dose UFH protocols studied. Although Heparin Anticoagulation Randomized Trial in Cardiac Catheterization (HEARTCAT) was not designed as non-inferiority trial, low-dose UFH (50 units kg(-1) bolus) appears sufficient for thromboprophylaxis during CC.

Intercoronary collateral flow detected by Doppler colour flow mapping is an additional diagnostic sign in children with anomalous origin of the left coronary artery from the pulmonary artery.

Intercoronary collateral flow within septal collaterals was detected by colour-coded Doppler echocardiography in three children with anomalous origin of the left coronary artery from the pulmonary artery. In each of the three patients angiography confirmed the presence of septal collaterals.

Is there a possible role for haemostasis in the development of perigraft reaction complicating the modified Blalock Taussig shunt?

The perigraft reaction is an unusual complication found in patients in whom a modified Blalock Taussig shunt has been created using a polytetrafluoroethylene graft. We found that, in two infants, consistent laboratory findings during such a perigraft reaction were hypofibrinogenemia, increased levels of thrombin-antithrombin III complex, prothrombin fragment 1 and 2 and products of degradation of fibrin. Normalization of the levels of fibrinogen produced resolution of the perigraft reaction.

[Bacterial endocarditis in childhood]. / Bakterielle Endokarditis im Kindesalter.

BACKGROUND: Bacterial endocarditis in childhood is a rare but serious disease. The group of children with congenital heart disease at risk to develop bacterial endocarditis increases, because more children survive with advanced medical and surgical management. Rheumatic Fever as predisposing heart disease decreases and is of reduced importance. PATIENTS: From 1983 to 1993 16 patients in the age of 0.3 to 17.6 years (mean 10.6 years) were received by the Department of Pediatric Cardiology of the University Children's Hospital Vienna with the diagnosis "bacterial endocarditis". A congenital heart disease was known previously in 13 cases: 4 children had VSD, 2 children had Tetralogy of Fallot, 1 child had a single ventricle and an infundibular pulmonary stenosis, 4 children had pulmonary atresia, 1 child had a cleft of the mitral valve, and 1 child had a coronary artery fistula. Moreover, 1 child had a mitral valve prolapse with valvular regurgitation as a consequence of Marfan-Syndrome. 6 children with congenital heart disease had been treated surgically previously. METHODS: Medical data of all patients with the diagnosis of "bacterial endocarditis" between 1983 and 1993 were analysed. It was this period when echocardiography was used for the first time to contribute to diagnosis and course control. RESULTS: In 11 of 16 cases positive blood cultures were obtained. Mostly Streptococcus viridans (4 cases) and Staphylococcus aureus (3 cases) were isolated. During the parenteral therapy with antibiotics 9 children suffered as a side effect from a drug induced fever and/or decreasing leucocytes and thrombocytes or a rash. In addition to the antibiotic therapy 8 children were treated surgically. One child died immediatly after the operation. 15 of the 16 patients with endocarditis survived. CONCLUSIONS: With children with known heart disease the recommendations for the prevention of bacterial endocarditis have to be strictly followed and every long ongoing feverish disease has to be carefully examinated.

Pediatric cardiac extracorporeal membrane oxygenation in congenital heart disease: the cardiologist's view.

There is no doubt that extracorporeal membrane oxygenation (ECMO) as a powerful therapeutic modality in critically ill newborn infants and older children with congenital heart disease has implications for the pediatric cardiologist. His responsibilities as consultant in the intensive care unit include screening for unsuspected cyanotic heart disease in neonatal candidates referred for ECMO and appraisal of surgical repair in postcardiotomy patients as well as assessment of postoperative hemodynamics and detection of complications during perfusion. A close cooperation between intensive care specialists and other appropriate specialists (pediatric cardiologists, cardiac surgeons, and anesthesiologists) is required for the process of decision making prior to initiation of postoperative ECMO in the individual patient with congenital heart disease. Long-term survival, morbidity, cerebrovascular complications, and neurodevelopmental sequelae of these near miss children remain a critical issue. Furthermore, there is a strong need for professional psychosocial support of affected parents, both in the hospital and after discharge.

Extracorporeal life support in pediatric patients with heart failure.

The prognosis of patients with end-stage heart failure presenting with acute clinical deterioration is poor. Extracorporeal membrane oxygenation (ECMO), however, can provide univentricular and biventricular cardiac support which has led to the extended application of ECMO to infants and children. With improving results, indications and modalities of mechanical support have changed, and mechanical bridge to cardiac transplantation will offer extended survival for selected patients. The purpose of this article is to provide comprehensive data of pediatric cardiac support and to discuss the central role of echocardiography in the estimation of cardiac performance during mechanical support. As a conclusion, one can predict that the encouraging results of today will lead to further technological developments, which will create individual technical solutions of different clinical applications.

Two-dimensional and Doppler echocardiographic follow-up after the arterial switch operation for transposition of the great arteries.

An echocardiographic follow-up examination was performed in 20 children who underwent an arterial switch operation from November 1984 to October 1990. The age at the time of operation ranged from 1 to 54 days, the weight ranged from 2.5 to 4.5 kg body weight. The time interval from the day of operation and the examination ranged from 3 to 74 months. M-mode echocardiography showed hypokinetic left ventricular function in 6 patients (30%). Abnormal segmental left ventricular wall motions were found in 6/16 patients (37.5%). Doppler echocardiographic examination at the site of the pulmonary anastomosis revealed an instantaneous gradient less than 20 mmHg in 9 patients (45%), a gradient between 20 and 60 mmHg in 9 patients (45) and a gradient greater than 60 mmHg in two patients (10%). The location of the stenosis was just below the bifurcation in 17 patients (85%) and seemed to be related to stretching of the pulmonary trunk during the Lecompte maneuver. One patient (5%) had a supravalvular aortic stenosis with a gradient of 43 mmHg. Color-flow mapping revealed mild aortic regurgitation in 8 patients (40%) but moderate regurgitation in one patient (5%). Three patients (15%) showed mild mitral regurgitation, all of them also had hypokinetic left ventricular function.