Left Ventricular Physiology and Ventricular-Vascular Interactions in Young Patients After Heart Transplantation.

Background In patients after heart transplantation, systemic arterial hypertension and enhanced central aortic stiffness contribute to increased ventricular afterload, which might lead to graft dysfunction. The aim of our study was to characterize systemic arterial elastance and its impact on left ventricular function and ventriculo-arterial coupling in a cohort of children, adolescents, and young adults after heart transplantation using invasive conductance catheter technique. Methods and Results Thirty patients who had heart transplants (age, 20.0±6.5 years, 7 female) underwent invasive cardiac catheterization including pressure-volume loop analysis. Load-independent parameters of systolic (ventricular elastance [Ees]) and diastolic (ventricular compliance) function as well as systemic arterial elastance (Ea, end-systolic pressure/stroke volume) and ventriculo-arterial coupling (Ea/Ees) were assessed at baseline level and during dobutamine infusion (10 µg/kg/min). Ees showed an appropriate increase under inotropic stimulation from 0.43 (0.11-2.52) to 1.00 (0.20-5.10) mm Hg/mL/m2 (P<0.0001), whereas ventricular compliance remained rather unchanged (0.16±0.10 mm Hg/mL/m2 to 0.12±0.07 mm Hg/mL/m2; P=0.10). Ventriculo-arterial coupling Ea/Ees was abnormal at rest and did not improve significantly under dobutamine (1.7 [0.6-6.7] to 1.3 [0.5-4.9], P=0.70) due to a simultaneous rise in Ea from 0.71 (0.37-2.82) to 1.10 (0.52-4.03) mm Hg/mL/m2 (P<0.0001). Both Ees and ventricular compliance were significantly associated with Ea at baseline and under dobutamine infusion. Conclusions Patients who underwent heart transplantation show impaired ventriculo-arterial coupling at rest and under inotropic stimulation despite preserved left ventricular contractile reserve. An abnormal response in vascular function resulting in increased afterload seems to represent an important factor that may play a role for the development of late graft failure.

Optimal septum alignment of the Figulla Flex occluder to the atrial septum in patients with secundum atrial septal defects.

AIMS: To investigate the implantation safety, anatomic performance and septal alignment of the Occlutech Figulla Flex occluder (FFO) device, an atrial septal defect (ASD) closure device with specific left-sided deployment characteristics and right-sided septal alignment properties. METHODS AND RESULTS: Between January 2011 and December 2013 we prospectively collected the change of orientation of the device to the septum during the release process and the feasibility of implantation of the FFO in 122 patients. The mean age was 10.7 years (±10.2), weight 32.9 kg (±20.3), and height 129.4 cm (±30). Devices used were 9 (n=13), 10.5 (n=16), 12 (n=16), 15 (n=39), 18 (n=17), 21 (n=8), 24 (n=5), 27 (n=7) and 30 mm (n=3) in size. No additional implantation techniques were required. Before release, the mean angles of the left and right-sided discs were 29.2° (±9.9°) and 43.4° (±9.2°) to the body axis, and 18.7° (±8.7°) and 27.0° (±10°) immediately thereafter. Thus, there was only a slight change in orientation of the left-sided (10.6°±7.5°) and right-sided (16.3°±7.9°) discs. CONCLUSIONS: The design of this occluder system results in an ideal septum alignment which increases its feasibility as well as patient safety during implantation.

Effect of Inhaled Nitric Oxide on Blood Flow Dynamics in Patients After the Fontan Procedure Using Cardiovascular Magnetic Resonance Flow Measurements.

Invasive hemodynamic studies have shown that nitric oxide (NO), a selective pulmonary vasodilator, can lower pulmonary vascular resistance in Fontan patients. Because oximetry-derived flow quantification may be unreliable, we sought to detect changes in blood flow within the Fontan circulation after inhalation of NO using cardiovascular magnetic resonance (CMR). Thirty-three patients (mean age 12.8 ± 7.0 years) after the Fontan procedure underwent CMR as part of their routine clinical assessment. Standard two-dimensional blood flow measurements were performed in the Fontan tunnel, superior vena cava (SVC) and ascending aorta (AAO) before and after inhalation of 40 ppm NO for 8-10 min. Systemic-to-pulmonary collateral (SPC) flow was calculated as AAO - (SVC + tunnel). Heart rate (82 ± 18 to 81 ± 18 bpm; p = 0.31) and transcutaneous oxygen saturations (93 ± 4 to 94 ± 3 %; p = 0.13) did not change under NO inhalation. AAO flow (3.23 ± 0.72 to 3.12 ± 0.79 l/min/m(2); p = 0.08) decreased, tunnel flow (1.58 ± 0.40 to 1.65 ± 0.46 l/min/m(2); p = 0.032) increased, and SVC flow (1.01 ± 0.39 to 1.02 ± 0.40 l/min/m(2); p = 0.50) remained unchanged resulting in higher total caval flow (Qs) (2.59 ± 0.58 to 2.67 ± 0.68 l/min/m(2); p = 0.038). SPC flow decreased significantly from 0.64 ± 0.52 to 0.45 ± 0.51 l/min/m(2) (p = 0.002) and resulted in a significant decrement of the Qp/Qs ratio (1.23 ± 0.23 to 1.15 ± 0.23; p = 0.001). Inhalation of NO in Fontan patients results in significant changes in pulmonary and systemic blood flow. The reduction in SPC flow is accompanied by a net increase in effective systemic blood flow suggesting beneficial effects of pulmonary vasodilators on cardiac output, tissue perfusion and exercise capacity.

Creation of a transcatheter fenestration in children with failure of Fontan circulation: Focus on extracardiac conduit connection.

OBJECTIVES: We report our experience with a transcatheter technique to bypass the lung and to thus improve single-ventricle preload and reduce venous congestion in Fontan patients. BACKGROUND: In the absence of a dedicated power source to serve the pulmonary circulation and a significantly elevated transpulmonary pressure gradient, fenestration of the Fontan circulation is an option to improve hemodynamics in patients by relieving excessive systemic venous pressure. METHODS AND RESULTS: From 2005 to 2011, 22 transcatheter fenestrations were performed without any major complications in 19 patients (median age 3.2 years, interquartile range (IQR) 2.7-3.7 years)) with failing Fontan circulation and exceeding systemic venous pressure. In 16 patients, the procedure was performed for acute postoperative failure 1-24 days after surgery. After perforation of the conduit and atrial wall by a Brockenbrough needle and gradual balloon dilation, premounted stents were expanded to create a diabolo configuration with flaring stent edges, leaving a slight but definitive central waist. The procedure resulted in regression of pleural effusions and a significant decrease in systemic venous pressure. Clinical improvement was observed in 16 of the 19 treated patients. Follow-up demonstrated sustained fenestration in 85% of treated patients for at least 24 months. CONCLUSION: Transcatheter creation of a Fontan fenestration is a safe approach despite the anatomic gap between the extracardiac conduit cavity and the atrial wall. Stent implantation allows defining the diameter of the fenestration, reduces spontaneous occlusion, and ensures sustained clinical improvement.

Focal myocardial fibrosis assessed by late gadolinium enhancement cardiovascular magnetic resonance in children and adolescents with dilated cardiomyopathy.

BACKGROUND: Different patterns of late gadolinium enhancement (LGE) including mid-wall fibrosis using cardiovascular magnetic resonance (CMR) have been reported in adult patients presenting with non-ischemic dilated cardiomyopathy (DCM). In these studies, LGE was associated with pronounced LV remodelling and predicted adverse cardiac outcomes. Accordingly, the purpose of our study was to determine the presence and patterns of LGE in children and adolescents with DCM. METHODS: Patients <18 years of age presenting with severe congestive heart failure who were admitted for evaluation of heart transplantation at our centre underwent CMR examination which consisted of ventricular functional analysis and assessment of LGE for detection of myocardial fibrosis. Ischemic DCM was excluded by coronary angiography, and right ventricular endomyocardial biopsies ruled out acute myocarditis. RESULTS: Thirty-one patients (mean age 2.1 ± 4.2 years) with severe LV dilatation (mean indexed LVEDV 136 ± 48 ml/m(2)) and LV dysfunction (mean LV-EF 23 ± 8%) were examined. LGE was detected in 5 of the 31 patients (16%) appearing in various patterns characterized as mid-wall (n = 1), focal patchy (n = 1), RV insertion site (n = 1) and transmural (n = 2). Based on histopathological analysis, 4 of the 5 LGE positive patients had lymphocytic myocarditis, whereas one patient was diagnosed with idiopathic DCM. CONCLUSIONS: In children and adolescents with DCM, focal histologically proven myocardial fibrosis is rarely detected by LGE CMR despite marked LV dilatation and severely depressed LV function. LGE occurred in various patterns and mostly in patients with inflammatory cardiomyopathy. It remains unclear whether myocardial fibrosis in childhood DCM reflects different endogenous repair mechanisms that enable favourable reverse remodelling. Larger trials are needed to assess the prognostic implications of LGE in childhood DCM.

Transcatheter Closure of Perimembranous Ventricular Septal Defects with Left Ventricular to Right Atrial Shunt.

During the development of so-called aneurysmal transformation of perimembranous ventricular septal defects (pmVSD), tricuspid valve (TV) morphology and function may be altered resulting in left ventricular (LV) to right atrial (RA) shunting. The feasibility and outcome of interventional closure of these pmVSD has not been investigated so far. Interventional closure of pmVSD associated with mild to moderate LV-to-RA shunt was performed in four patients (aged 6.5-12.5 years). pmVSD were closed under fluoroscopic guidance by establishing an arteriovenous wire loop via a femoral artery and advancing the delivery sheath from a femoral vein. Before device release (or withdrawal if necessary), residual shunting across the device and TV valve function was investigated by transthoracic echocardiography and LV angiography. pmVSD sizes of 4, 5.5, 8 and 8.5 mm were closed with a 4/4 and 6/6 Amplatzer duct occluder II and an 8- and 10-mm Amplatzer muscular VSD occluder device, respectively. There were no or only minor residual postinterventional LV-to-RA shunts. No atrioventricular blocks were observed during a mean follow-up of 12.5 months (range 6.5-17 months). Transthoracic echocardiography indicated that the elimination of the VSD jet pushing the antero-superior TV leaflet open is the key mechanism for LV-to-RA shunt reduction after transcatheter pmVSD closure. Interventional closure in pmVSD associated with mild to moderate indirect LV-to-RA shunting is feasible and results in significant reduction in or elimination of LV-to-RA shunting.

Implantation of the new Nit-Occlud PDA-R device in children below 10 kilogram.

BACKGROUND: Interventional closure of patent ductus arteriosus (PDA) has become a common and safe procedure in most pediatric cath labs. Interventional treatment of PDAs still remains a challenge in those children with low body weight and a large PDA. The Nit-Occlud PDA-R® device was developed and especially designed for large PDAs. We report our most recent experience in children with a body weight lower than 10 kg. MATERIALS AND METHODS: The PDA-R® device was used in seven children (age 1-10, median 6 months) with a body weight from 4.1 to 9.7 kg (median 5.9 kg): ductal length was 12 mm (median), with a large ampulla (median 9 mm) which exceeded the diameter of the aorta (median 6 mm) and large diameter (median minimal diameter 4 mm). In six cases, the Nit-Occlud PDA-R was selected with an aortic disc of 12 mm and in one case an occluder with an aortic disc of 14 mm. RESULTS: Occlusion of the PDA was documented by angiography and/or echocardiography in all cases. At a mean follow-up of 21.4 months, no flow obstruction to the left or right pulmonary artery or new onset coarctation of the aorta was noted. CONCLUSIONS: The Nit-Occlud PDA-R® device is suitable in children with a body weight below 10 kg when a relative large PDA is present.

Compression, distortion and dislodgement of large caliber stents in congenital heart defects caused by cardiopulmonary resuscitation: a case series and review of the literature.

Stenting of vascular, extracardiac or lately intracardiac stenosis has become an established interventional treatment for a variety of problems in congenital or acquired heart disease. Most stent procedures are completed successfully and the long-term outcome is favorable in the majority of cases. Stent collapse or deformation is a well recognized entity in peripheral stents and can be attributed to insufficient radial force; it can also be attributed to excessive external forces, like deformation of stents in the right ventricular outflow tract, where external compression is combined with continuous movement caused by the beating heart. The protection of the thoracic cage may prove to be insufficient in extraordinary circumstances, such as chest compression in trauma or cardiopulmonary resuscitation (CPR). In this case series, we describe three patients in whom large endovascular stents were placed to treat significant stenosis of the aorta, the aortic arch or the venous system of the inferior vena cava close to the atrium. In all patients, CPR was necessary during their clinical course for various reasons; after adequate CPR, including appropriate chest compression all patients survived the initial resuscitation phase. Clinical, echocardiographic as well as radiologic re-evaluation after resuscitation revealed significant stent distortion, compression, displacement or additional vascular injury. The possibility of mechanical deformation of large endovascular stents needs to be considered and recognized when performing CPR; if CPR is successful, immediate re-evaluation of the implanted stents--if possible by biplane fluoroscopy--seems mandatory.

Creation of a functional Potts shunt by stenting the persistent arterial duct in newborns and infants with suprasystemic pulmonary hypertension of various etiologies.

BACKGROUND: The surgical creation of a Potts shunt has been reported in children with suprasystemic idiopathic pulmonary artery (PA) hypertension (IPAH) refractory to any medical therapy. This surgical approach allows acute decompression of the right ventricle (RV) and thereby avoids ventricular failure. We present 4 newborns and infants with different causes of pulmonary hypertension (PH) in whom interventional stenting of the patent ductus arteriosus (PDA) was used to create a "functional" Potts shunt. METHODS: Suprasystemic PH was diagnosed by cardiac catheterization in 2 newborns with complex left heart obstructive lesions, a patient with persistent PH of the newborn (PPHN), and an infant with IPAH and was accompanied by RV dilation and imminent RV failure. RESULTS: Stenting of the PDA was performed uneventfully during cardiac catheterization in all patients and led to stabilization of clinical symptoms. The 2 patients with complex cardiac lesions subsequently underwent successful biventricular repair. In the PPHN patient, the stented PDA was closed interventionally when PA pressures dropped and a significant left-to-right shunt occurred. PA pressures in the patient with IPAH remained high while the stented PDA still served as RV decompression in avoidance of lung transplantation. CONCLUSIONS: Newborns and infants with suprasystemic PH of varying etiologies may benefit from the creation of a functional Potts shunt by stenting the PDA. This strategy should be considered in patients with suprasystemic IPAH or PPHN as a temporary or permanent therapy when a PDA can be identified at cardiac catheterization. It may also be beneficial in patients with PH due to left heart obstructions by serving as a bridge to further corrective surgery.

Percutaneous closure of atrial septal defects in spontaneously breathing children under deep sedation: a feasible and safe concept.

Interventional cardiac catheterization in children and adolescents is traditionally performed with the patient under general anesthesia and endotracheal intubation. However, percutaneous closure of atrial septum defect (ASD) without general anaesthesia is currently being attempted in a growing number of children. The study objective was to evaluate the success and complication rate of percutaneous ASD closure in spontaneously breathing children under deep sedation. Retrospective single centre cohort study of consecutive children undergoing percutaneous ASD closure at a tertiary care pediatric cardiology centre. Transesophageal echocardiography (TEE) and percutaneous ASD closure were performed with the patient under deep sedation with intravenous bolus of midazolam and ketamine for induction and propofol continuous infusion for maintenance of sedation in spontaneously breathing children. One hundred and ninety-seven patients (median age 6.1 years [minimum 0.5; maximum 18.8]) underwent TEE and ASD balloon sizing. Percutaneous ASD closure was attempted in 174 patients (88 %), and device implantation was performed successfully in 92 %. To achieve sufficient deep sedation, patients received a median ketamine dose of 2.7 mg/kg (0.3; 7) followed by a median propofol continuous infusion rate of 5 mg/kg/h (1.1; 10.7). There were no major cardiorespiratory complications associated with deep sedation, and only two patients (1 %) required endotracheal intubation due to bronchial obstruction immediately after induction of sedation. Seventeen patients (8 %) had minor respiratory complications and required frequent oral suctioning or temporary bag-mask ventilation. TEE and percutaneous ASD closure can be performed safely and successfully under deep sedation in spontaneously breathing children of all ages.

Evaluation of left ventricular torsion in children with hypertrophic cardiomyopathy.

AIMS: To evaluate the role of torsion in hypertrophic cardiomyopathy in children. METHODS: A total of 88 children with idiopathic hypertrophic cardiomyopathy (n = 24) and concentric hypertrophy (n = 20) were investigated with speckle-tracking echocardiography and compared with age- and gender-matched healthy controls (n = 44). RESULTS: In hypertrophic cardiomyopathy, we found increased torsion (2.8 ± 1.6 versus 1.9 ± 1.0°/cm [controls], p < 0.05) because of an increase in clockwise basal rotation (-8.7 ± 4.3° versus -4.9 ± 2.5° [controls], p < 0.001) and prolonged time to peak diastolic untwisting (3.7 ± 2.4% versus 1.7 ± 0.6% [controls] of cardiac cycle, p < 0.01), but no differences in peak untwisting velocities. Hypertrophic cardiomyopathy patients demonstrated a negative correlation between left ventricular muscle mass and torsion (r = -0.7, p < 0.001). In concentric hypertrophy, torsion was elevated because of increased apical rotation (15.1 ± 6.4° versus 10.5 ± 5.5° [controls], p < 0.05) without correlation with muscle mass. Peak untwisting velocities (- 202 ± 88 versus -145 ± 67°/s [controls], p < 0.05) were higher in concentric hypertrophy and time to peak diastolic untwisting was delayed (1.8 ± 0.8% versus 1.2 ± 0.6% [controls], p < 0.05). CONCLUSIONS: In contrast to an increased counterclockwise apical rotation in concentric hypertrophy, hypertrophic cardiomyopathy is characterised by predominantly enhanced systolic basal clockwise rotation. Diastolic untwisting is delayed in both groups. Torsion may be an interesting marker to guide patients with hypertrophic cardiomyopathy.

Stenting of the right ventricular outflow tract in symptomatic neonatal tetralogy of Fallot.

There is ongoing debate regarding the initial management of symptomatic neonates with tetralogy of Fallot. Although neonatal repair can be performed with low mortality, it is associated with increased morbidity and long-term impact on right ventricular performance. Traditionally, the modified Blalock-Taussig shunt remains the palliative procedure of choice. Differential pulmonary artery flow may occur and subsequently result in underdevelopment and distortion of pulmonary vessels. Transcatheter therapy was previously limited to balloon valvulotomy when the obstruction is predominantly at the pulmonary valve level. Stenting of the right ventricular outflow tract can enable adequate forward flow; however, pulmonary regurgitation may impact on right ventricular performance and cardiac output. Stenting of the right ventricular outflow tract with valve sparing placement of the stent thus treating the underlying pathophysiology of the hypercyanotic spells provides a safe and effective management strategy, improving arterial oxygen saturation, avoiding pulmonary regurgitation and encouraging pulmonary artery growth.

Percutaneous implantation of the Edwards SAPIEN(™) pulmonic valve: initial results in the first 22 patients.

BACKGROUND: Percutaneous pulmonary valve implantation (PPVI) was introduced in 2000 as an interventional procedure for the treatment of right ventricular outflow tract (RVOT) dysfunction. The new Edwards SAPIEN(™) pulmonic valve has reached CE certification at the end of 2010 thus offering an attractive alternative with extended sizes (23 and 26 mm) to the conventional Melody(®) valve (sizes 18, 20 and 22 mm). PATIENTS: Over a 1-year period, PPVI using the Edwards SAPIEN(™) pulmonic valve was performed in 22 patients using a standardized procedure. Primary diagnosis was tetralogy of Fallot (n = 11), pulmonary atresia (n = 2), Truncus arteriosus (n = 3), TGA/PS-Rastelli (n = 1), Ross surgery (n = 2), double outlet right ventricle (n = 2) and absent pulmonary valve syndrome (n = 1). The character of the RVOT for PPVI was transannular patch (n = 4), bioprosthesis (n = 2), homograft (n = 5) and Contegra(®) conduit (n = 11). The leading hemodynamic problem consisted of a pulmonary stenosis (PS) (n = 2), pulmonary regurgitation (PR) (n = 11) and a combined PS/PR lesion (n = 9). RESULTS: In 21/22 patients, PPVI was performed successfully (10 × 23 and 11 × 26 mm). There were 9 female and 13 male patients; the mean age was 21.7 years (range 6-83 years), the mean length was 162 cm (range 111-181 cm) and the weight 56.5 kg (range 20-91 kg). Invasive data showed a decrease of RV-systolic pressure from 61.2 mmHg (± 23.1) to 41.2 mmHg (± 8.6) and reduction of RV-PA gradient from 37.3 mmHg (± 23.2) to 6.9 mmHg (± 5.3). The PA-systolic pressure increased from 25.8 mmHg (± 8.6) to 33.9 mmHg (± 9.3) as did the PA diastolic pressure (from 6.0 mmHg (± 5.6) to 14.6 mmHg (± 4.3). There was a substantial reduction of pulmonary regurgitation from before (none/trivial n = 0, mild n = 2, mode rate n = 9, severe n = 11) to after PPVI (none/trivial n = 20, mild n = 1). During the short-term follow-up of 5.7 months there was no change in the immediate results. CONCLUSION: PPVI using the Edwards SAPIEN(™) pulmonic valve can be performed safely in a wide range of patients with various diagnoses and underlying pathology of the RVOT and enables the restoration of an adult-size RVOT diameter. Although the immediate and short-term results seem promising, the long-term effects and safety have to be assessed in further clinical follow-up studies.

Feasibility and efficacy of stent redilatation in aortic coarctation.

OBJECTIVES: We evaluated the efficacy and safety of stent redilation in patients with aortic coarctation (COA). METHODS AND RESULTS: In our retrospective study of 28 stent redilation procedures on 22 patients, the interval between implantation and redilation ranged from 2.5 month to 11 years (median 18 months). Ten patients had native COAs, one had repaired interrupted aortic arch. The remaining patients had residual COAs after surgery. Stent redilation was successful in 26 procedures. Pressure gradients decreased from a mean of 26 +/- 13.8 mm Hg to 7.9 +/- 6.52 mm Hg (P < 0.001). The mean diameter of the stents increased from 9.19 +/- 3.29 mm to 12.1 +/- 3.68 mm (P < 0.001). In a patient with Williams-Beuren syndrome, massive neointimal proliferation made stent redilation impossible. One other patient developed aortic aneurysm after redilation and was operated after 3 years. CONCLUSIONS: Stent redilation for aortic COA is a safe and successful procedure.

Oxygen causes cell death in the developing brain.

Substantial neurologic morbidity occurs in survivors of premature birth. Premature infants are exposed to partial oxygen pressures that are fourfold higher compared to intrauterine conditions, even if no supplemental oxygen is administered. Here we report that short exposures to nonphysiologic oxygen levels can trigger apoptotic neurodegeneration in the brains of infant rodents. Vulnerability to oxygen neurotoxicity is confined to the first 2 weeks of life, a period characterized by rapid growth, which in humans expands from the sixth month of pregnancy to the third year of life. Oxygen caused oxidative stress, decreased expression of neurotrophins, and inactivation of survival signaling proteins Ras, extracellular signal-regulated kinase (ERK 1/2), and protein kinase B (Akt). The synRas-transgenic mice overexpressing constitutively activated Ras and phosphorylated kinases ERK1/2 in the brain were protected against oxygen neurotoxicity. Our findings reveal a mechanism that could potentially damage the developing brain of human premature neonates.

Pathways leading to apoptotic neurodegeneration following trauma to the developing rat brain.

Trauma triggers diffuse apoptotic neurodegeneration in the developing rat brain. To explore the pathogenesis of this phenomenon we investigated the involvement of three possible mechanisms: death receptor activation, activation of the intrinsic apoptotic pathway by cytochrome c release into the cytoplasm, and changes in trophic support provided by endogenous neurotrophins. We detected a decrease in the expression of bcl-2 and bcl-x(L), two antiapoptotic proteins that decrease mitochondrial membrane permeability, an increase in cytochrome c immunoreactivity in the cytosolic fraction, and an activation of caspase-9 in brain regions which show apoptotic neurodegeneration following percussion brain trauma in 7-day-old rats. Increase in the expression of the death receptor Fas was revealed by RT-PCR analysis, Western blotting, and immunohistochemistry, as was activation of caspase-8 in cortex and thalamus. Apoptotic neurodegeneration was accompanied by an increase in the expression of BDNF and NT-3 in vulnerable brain regions. The pancaspase inhibitor z-VAD.FMK ameliorated apoptotic neurodegeneration with a therapeutic time window of up to 8 h after trauma. These findings suggest involvement of intrinsic and extrinsic apoptotic pathways in neurodegeneration following trauma to the developing rat brain. Upregulation of neurotrophin expression may represent an endogenous mechanism that limits this apoptotic process.

Fas (CD95/Apo-1)/Fas ligand expression in neonates with pontosubicular neuron necrosis.

Pontosubicular neuron necrosis (PSN) represents an age-specific response to severe hypoxic-ischemic injury occurring in human neonates but not in older children or adults. Histologically, PSN is characterized by acute neuronal death in the pontine nuclei and the hippocampal subiculum bearing the hallmarks of apoptosis. In animal models of hypoxic-ischemic injury, induction of neuronal apoptosis can be triggered by Fas (CD95/Apo-1), a cell surface receptor of the tumor necrosis factor-alpha superfamily, which transduces apoptotic death signals when cross-linked by its natural ligand. Here, we have investigated the expression of Fas/Fas ligand in human autopsy material consisting of 13 PSN cases and 10 age-matched cases without PSN. Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling, immunohistochemistry, and double labeling for Fas/Fas ligand and the astrocyte marker glial fibrillary acid protein, the microglia/macrophage specific marker KiM1P, and the neuronal marker NeuN were performed on formalin-fixed brain specimens. Although mainly neurons of both PSN and controls expressed Fas receptor, expression was significantly increased (p = 0.001) in PSN cases in which predominantly degenerating cells with signs of early apoptosis showed Fas expression. In contrast, Fas ligand expression was found mainly on astrocytes and microglial cells. There was no significant difference between cases with and without PSN. We conclude that in the developing human brain, cells expressing the Fas receptor may be susceptible to undergoing apoptosis in response to hypoxic-ischemic injury.