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Background & Aims: Pathological bacterial translocation (PBT) in cirrhosis is the hallmark of spontaneous bacterial infections, increasing mortality several-fold. Increased intestinal permeability is known to contribute to PBT in cirrhosis, although the role of the mucus layer has not been addressed in detail. A clear route of translocation for luminal intestinal bacteria is yet to be defined, but we hypothesize that the recently described gut-vascular barrier (GVB) is impaired in experimental portal hypertension, leading to increased accessibility of the vascular compartment for translocating bacteria., Materials: Cirrhosis was induced in mouse models using bile-duct ligation (BDL) and CCl 4 . Pre-hepatic portal-hypertension was induced by partial portal vein ligation (PPVL). Intestinal permeability was compared in these mice after GFP-Escherichia coli or different sized FITC-dextrans were injected into the intestine., Results: Healthy and pre-hepatic portal-hypertensive (PPVL) mice lack translocation of FITC-dextran and GFP-E. coli from the small intestine to the liver, whereas BDL and CCl 4 -induced cirrhotic mice demonstrate pathological translocation, which is not altered by prior thoracic-duct ligation. The mucus layer is reduced in thickness, with loss of goblet cells and Muc2-staining and expression in cirrhotic but not PPVL mice. These changes are associated with bacterial overgrowth in the inner mucus layer and pathological translocation of GFP-E. coli through the ileal epithelium. GVB is profoundly altered in BDL and CCl 4 -mice with Ileal extravasation of large-sized 150 kDa-FITC-dextran, but only slightly altered in PPVL mice. This pathological endothelial permeability and accessibility in cirrhotic mice is associated with augmented expression of PV1 in intestinal vessels. OCA but not fexaramine stabilizes the GVB, whereas both FXR-agonists ameliorate gut to liver translocation of GFP-E. coli., Conclusions: Cirrhosis, but not portal hypertension per se, grossly impairs the endothelial and muco-epithelial barriers, promoting PBT to the portal-venous circulation. Both barriers appear to be FXR-modulated, with FXR-agonists reducing PBT via the portal-venous route., Lay Summary: For intestinal bacteria to enter the systemic circulation, they must cross the mucus and epithelial layer, as well as the gut-vascular barrier. Cirrhosis disrupts all 3 of these barriers, giving bacteria access to the portal-venous circulation and thus, the gut-liver axis. Diminished luminal bile acid availability, cirrhosis and the associated reduction in farnesoid x receptor (FXR) signaling seem, at least partly, to mediate these changes, as FXR-agonists reduce bacterial translocation via the portal-venous route to the liver in cirrhosis., (Copyright © 2019 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background & Aims: Fatty liver disease, including non-alcoholic fatty liver (NAFLD) and steatohepatitis (NASH), has been associated with increased intestinal barrier permeability and translocation of bacteria or bacterial products into the blood circulation. In this study, we aimed to unravel the role of both intestinal barrier integrity and microbiota in NAFLD/NASH development., Methods: C57BL/6J mice were fed with high-fat diet (HFD) or methionine-choline-deficient diet for 1 week or longer to recapitulate aspects of NASH (steatosis, inflammation, insulin resistance). Genetic and pharmacological strategies were then used to modulate intestinal barrier integrity., Results: We show that disruption of the intestinal epithelial barrier and gut vascular barrier (GVB) are early events in NASH pathogenesis. Mice fed HFD for only 1 week undergo a diet-induced dysbiosis that drives GVB damage and bacterial translocation into the liver. Fecal microbiota transplantation from HFD-fed mice into specific pathogen-free recipients induces GVB damage and epididymal adipose tissue enlargement. GVB disruption depends on interference with the WNT/β-catenin signaling pathway, as shown by genetic intervention driving β-catenin activation only in endothelial cells, preventing GVB disruption and NASH development. The bile acid analogue and farnesoid X receptor agonist obeticholic acid (OCA) drives β-catenin activation in endothelial cells. Accordingly, pharmacologic intervention with OCA protects against GVB disruption, both as a preventive and therapeutic agent. Importantly, we found upregulation of the GVB leakage marker in the colon of patients with NASH., Conclusions: We have identified a new player in NASH development, the GVB, whose damage leads to bacteria or bacterial product translocation into the blood circulation. Treatment aimed at restoring β-catenin activation in endothelial cells, such as administration of OCA, protects against GVB damage and NASH development., Lay Summary: The incidence of fatty liver disease is reaching epidemic levels in the USA, with more than 30% of adults having NAFLD (non-alcoholic fatty liver disease), which can progress to more severe non-alcoholic steatohepatitis (NASH). Herein, we show that disruption of the intestinal epithelial barrier and gut vascular barrier are early events in the development of NASH. We show that the drug obeticholic acid protects against barrier disruption and thereby prevents the development of NASH, providing further evidence for its use in the prevention or treatment of NASH., (Copyright © 2019 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background: Down syndrome (DS) is the most common autosomal chromosomal anomaly in liveborn infants. About 40% of infants with DS have a major congenital heart defect (CHD). Among them, atrioventricular septal defects (AVSD), atrial septal defects (ASD), ventricular septal defect (VSD) and Tetralogy of Fallot (ToF) are the most common. The aim of this study was to estimate the sex difference in the occurrence of CHD in infants with DS comparing it with non-DS infants., Method: Live birth cases of DS diagnosed by the first year of life were extracted from the Registry of Congenital Anomalies of Tuscany (2003-2015 period). CHDs associated with DS were detected both from the registry and the hospital discharge data. Sex differences in total CHDs and ASD, VSD, AVSD, severe CHDs, ToF subgroups were investigated. Relative Risks between males and females (RR MF ) with p-values and 95% confidence interval (95% CI) were estimated. RR MF of CHD in infants with DS was compared to RR MF in infants without DS. The ratio between relative risks (RRR) was estimated., Results: A total of 230 live birth cases of DS were analyzed, with a prevalence of 5.70 per 10,000 births. Sex ratio MF was 1.3. One hundred and one DS cases (43.9%) were associated with at least one CHD. Among them, CHDs are more frequent in females (total CHD: RR MF  = 0.62; 95% CI: 0.46-0.83, ASD: RR MF  = 0.40; 95% CI: 0.21-0.77, severe CHD: RR MF  = 0.58; 95% CI: 0.35-0.95, AVSD: RR MF  = 0.57; 95% CI: 0.32-1.00, VSD: RR MF  = 0.59; 95% CI: 0.35-1.00). Four cases of ToF were observed (all males). Sex difference was more evident in DS than in non-DS infants (RRR = 0.63; 95% CI: 0.52-0.77), in particular for severe CHDs (RRR = 0.38; 95% CI: 0.25-0.57)., Conclusion: The increased sex difference for CHDs in DS suggests a possible role of sex as effect modifier in the association between DS and CHD. The results enforce the evidence on sex differences for CHDs in DS and can stimulate future genetic research activities., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Aim: To assess the acute results of the first human use of the Optimus covered stent in complex coarctation of the aorta., Methods and Results: We successfully implanted the Optimus covered stent in eight cases in patients whose preprocedural anatomy looked challenging for currently available covered stents. Six of the patients had native coarctation with one recoarctation following surgical repair. There were no significant complications with reduction in the mean invasive gradient from 22 to 1 mm Hg. The length of stents used ranged from 33 to 57 mm with a median shortening after expansion of 13%. Postprocedural follow-up with magnetic resonance imaging or computed tomography has not shown evidence of fracture or migration or renarrowing. The median duration of follow-up is 10 months., Conclusions: Preliminary results show that the Optimus covered stent is safe and efficacious for use in patients with coarctation of challenging morphology. A systemic trial will be required to evaluate this stent for more widespread practice., (© 2018 Wiley Periodicals, Inc.)

Background: Despite ventricular septal defects (VSDs) are the most common congenital heart diseases (CHDs) in the neonatal period, their incidence and natural history are still debated and their follow-up and management strategies remain controversial. Our aim was to evaluate the incidence and natural history of isolated VSDs., Methods: From January 1996 to December 2015 all neonates with a CHD suspicion were referred to the Cardiological Department of Grosseto Misericordia Hospital. Only newborns with confirmed isolated VSD were enrolled in this study and followed for 6 years., Results: Our 343 newborns with an isolated VSD (incidence of 10.45/1000/births) account for 64% of all detected CHDs. VSDs location were as follows: muscular (73.8%), perimembranous (11.3%), inlet (1%), and outlet (0.8%). Of the located VSDs, 90% were small, 7.5% moderate, and 2.5% large, respectively. Spontaneous closure was observed in 96 (29.2%) of the VSD patients at 6-month, 198 (60.2%) at 1-year, 261 (79.3%) at 2-year, and in 302 (91.8%) at 6-year follow-up. Risk factors for defect persistence were a perimembranous location (P = .001; HR: 0.508, CI: 0.342-0.755), detection of multiple defects (P = .043; HR: 0.728, CI: 0.536-0.990), and male gender (P < .048; HR: 0.783, CI: 0.615-0.998), respectively., Conclusions: We here provide an incidence and natural history of neonatal isolated VSDs in a neonatal Caucasian population. These data may be useful for the development of expert consensus/standard recommendation guidelines for the follow-up and VSD management, data that are currently lacking., (© 2017 Wiley Periodicals, Inc.)

Immune privilege is a complex process that protects organs from immune-mediated attack and damage. It is accomplished by a series of cellular barriers that both control immune cell entry and promote the development of tolerogenic immune cells. In this Review, we describe the vascular endothelial and epithelial barriers in organs that are commonly considered to be immune privileged, such as the brain and the eye. We compare these classical barriers with barriers in the intestine, which share features with barriers of immune-privileged organs, such as the capacity to induce tolerance and to protect from external insults. We suggest that when intestinal barriers break down, disruption of other barriers at distant sites can ensue, and this may underlie the development of various neurological, metabolic and intestinal disorders.

Background: Despite recent advances, current pediatric echocardiographic nomograms for valvular and arterial dimensions remain limited., Methods: We prospectively studied healthy Caucasian Italian children by two-dimensional (2D) echocardiography. Echocardiographic measurements for 18 valvular and arterial dimensions were performed and models were generated testing for linear, logarithmic, exponential, and square root relationships. Heteroscedasticity was accounted for by White or Breusch-Pagan test. Age, weight, height, heart rate, and body surface area (BSA) were used as independent variables in different analyses to predict the mean values of each measurement. Structured Z-scores were then computed., Results: In all, 1151 subjects (age 0 days to 17 years; 45% females; BSA 0.12-2.12m 2 ) were studied. The Haycock formula was used when presenting data as predicted values (mean±2 SDs) for a given BSA and within equations relating echocardiographic measurements to BSA. The predicted values and Z-score boundaries for all measurements are presented., Conclusions: We report echocardiographic nomograms for valvular and arterial dimensions derived from a large population of children. Integration of these data with those of previous reports would allow for a comprehensive coverage of pediatric 2D echocardiographic nomograms for measurement of 2D cardiac structures., (Copyright © 2016 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

It has been widely demonstrated that tolerance against gut microbiota is compartmentalized to mucosal sites where microbes mostly reside. How the commensal bacteria are excluded from the entrance into the blood stream via intestinal capillaries that are located beneath the gut epithelium was not clear. We recently described the existence of a new anatomical structure, the 'gut vascular barrier' (GVB), both in murine and human intestines that plays a fundamental role in avoiding indiscriminate trafficking of bacteria from the gut into the blood circulation. The vascular barrier integrity could be altered by Salmonella typhimurium, a pathogen capable of systemic dissemination, through the modulation of the Wnt/β-catenin signaling pathway. Here we have analyzed the differences in gut endothelial gene expression profiles during Salmonella infection and have identified some interesting characteristics of endothelial to mesenchymal transition. These findings add new insights in the gut-liver axis.

Background: Pediatric echocardiographic nomograms for systolic/diastolic functional indices are limited by small sample size and inconsistent methodologies. Our aim was to establish pediatric nomograms for mitral valve (MV) pulsed wave Doppler (PWD) and tissue Doppler imaging (TDI) velocities., Methods: We performed PWD/TDI measurements of MV velocities and generated models testing for linear/logarithmic/exponential/square root relationships. Heteroscedasticity was accounted for by White test or Breusch-Pagan test. Age, weight, height, heart rate (HR), and body surface area (BSA) were used as independent variables in different analyses to predict the mean values of each measurement., Results: In all, 904 Caucasian Italian healthy children (age 0 days-17 years; 45.5% females; BSA 0.12-2.12m(2)) were prospectively studied. No individual variable provided equations with an acceptable coefficient of determination (R(2)) and even the inclusion of multiple variables in the model resulted in only a partial amelioration of the R(2). Higher R(2) were obtained for PWD-E deceleration time (0.53), septal (Se') and lateral (Le') MV-TDI e' velocity (Se': 0.54; Le': 0.55). Variability was higher at lower age and BSA. In older children patterns were more reproducible; however, the exclusion of neonates did not substantially improve the final models. The low R(2) hampered building of z-scores and calculation of estimated percentiles. Thus normative data have been presented as observed percentile according to age for all measurements., Conclusions: We report normal ranges for PWD and TDI mitral velocities derived from a large population of Caucasian children. Variability of diastolic patterns especially at lower ages needs to be taken into account., (Copyright © 2015 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

We describe a case of transposition of the great arteries (TGA) with significant aortopulmonary collateral vessels causing management difficulties before and after an arterial switch operation. Preoperatively, the presence of collaterals exacerbated aortic diastolic runoff and led to myocardial ischemia. Postoperatively, despite uneventful extubation, the infant developed clinical heart failure characterized by pericardial and pleural effusions and feeding difficulties, which promptly resolved with percutaneous embolization of collaterals. Major aortopulmonary collaterals are rarely associated with TGA, but if present they may cause important hemodynamic imbalance in infants with TGA., (Copyright © 2016 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Cetuximab is a monoclonal antibody that is effective in the treatment of metastatic colorectal cancer (mCRC). Cetuximab blocks epidermal growth factor receptor (EGFR)-ligand interaction and inhibits downstream RAS-ERK activation. However, only some activating mutations in RAS affect cetuximab efficacy, and it is not clear what else mediates treatment success. Here we hypothesized that cetuximab induces immunogenic cell death (ICD) that activates a potent antitumor response. We found that cetuximab, in combination with chemotherapy, fostered ICD in CRC cells, which we measured via the endoplasmic reticulum (ER) stress response and an increase in phagocytosis by dendritic cells. ICD induction depended on the mutational status of the EGFR signaling pathway and on the inhibition of the splicing of X-box binding protein 1 (XBP1), an unfolded protein response (UPR) mediator. We confirmed the enhanced immunogenicity elicited by cetuximab in a mouse model of human EGFR-expressing CRC. Overall, we demonstrate a new, immune-related mechanism of action of cetuximab that may help to tailor personalized medicine.

In healthy individuals, the intestinal microbiota cannot access the liver, spleen, or other peripheral tissues. Some pathogenic bacteria can reach these sites, however, and can induce a systemic immune response. How such compartmentalization is achieved is unknown. We identify a gut-vascular barrier (GVB) in mice and humans that controls the translocation of antigens into the blood stream and prohibits entry of the microbiota. Salmonella typhimurium can penetrate the GVB in a manner dependent on its pathogenicity island (Spi) 2-encoded type III secretion system and on decreased β-catenin-dependent signaling in gut endothelial cells. The GVB is modified in celiac disease patients with elevated serum transaminases, which indicates that GVB dismantling may be responsible for liver damage in these patients. Understanding the GVB may provide new insights into the regulation of the gut-liver axis., (Copyright © 2015, American Association for the Advancement of Science.)

Cardiac catheterisation in congenital heart disease is a developing field. Patients' ages range from foetus to adulthood. This document is a revision and update of the previously published recommendations and summarises the requirements for training in diagnostic and interventional cardiac catheterisation.

Objectives: to estimate prevalence, mortality and lethality of congenital heart defects (CHDs), and to evaluate time trend by comparing two birth cohorts (1992- 2000 vs. 2001-2009)., Design: descriptive study using a population-based registry: the Tuscan Registry of congenital defects (RTDC), which is a member of the European network of surveillance of congenital anomalies (EUROCAT) since 1979., Setting and Participants: CHD cases were collected by the RTDC between 1992 and 2009., Main Outcome Measures: prevalence and mortality rates were calculated for all and non-chromosomal CHDs. The non-chromosomal cases were classified in three severity classes (SI, SII, SIII), according to decreasing perinatal mortality. It was estimated prevalence of: live births, foetal deaths (stillbirths and spontaneous abortions from 20 weeks gestation), terminations of pregnancy for foetal anomaly (TOPFAs) at any gestational age, and of prenatally diagnosed cases. Perinatal, neonatal and infant mortality were calculated. Early-neonatal, neonatal and infant lethality were calculated for the non-chromosomal cases., Results: 3,653 cases were identified out of 486,947 live births and 1,883 stillbirths, 95% of which were non-chromosomal cases. The total average prevalence was 7.47/1,000 births. The overall prevalence decreased significantly in all CHDs (Prevalence ratio - PR: 0.86; 95%CI 0.80-0.91) as well as in non-chromosomal (PR: 0.86; 95%CI 0.80-0.92), while in the more severe defects (SI/SII combined cases) the total prevalence was stable over time. In more severe cases, prevalence of live births decreased significantly (PR: 0.83; 95%CI 0.71-0.97), while the greater increase of TOPFAs and of diagnosed cases was observed in the prenatal period. All three mortality rates reduced significantly over time. In the more severe cases, the greatest rate mortality reduction was observed for neonatal mortality (Mortality ratio - MR: 0.29; 95%CI 0.16-0.49) than perinatal (MR: 0.37; 95%CI 0.19-0.70) and infant mortality (MR: 0,40; 95%CI 0.28-0.56). In this group of CHDs, early neonatal lethality decreased from 10% to 3%, neonatal lethality from 17% to 6%, and infant lethality from 24% to 10%., Conclusions: the results suggest that the improvements in prenatal diagnosis and in foetal and neonatal treatment and care have reduced the burden of congenital heart defects on the health of the Tuscany population.

Background: Although a quantitative evaluation of cardiac chamber dimensions in pediatric echocardiography is often important, nomograms for these structures are limited. The aim of this study was to establish reliable echocardiographic nomograms of cardiac chamber diameters and areas in a wide population of children., Methods: A total of 1,091 Caucasian Italian healthy children (age range, 0 days to 17 years; 44.8% female) with body surface areas (BSAs) ranging from 0.12 to 1.8 m(2) were prospectively enrolled. Twenty-two two-dimensional and M-mode measurements of atrial and ventricular chamber diameters and areas were performed. Models using linear, logarithmic, exponential, and square-root relationships were tested. Heteroscedasticity was tested by the White test and the Breusch-Pagan test. Age, weight, height, and BSA, calculated by the Haycock formula, were used as the independent variables in different analyses to predict the mean value of each echocardiographic measurement. The influence of various confounders, including gender, type of delivery, prematurity, and interobserver variability, was also evaluated. Structured Z scores were then computed., Results: The Haycock formula provided the best fit and was used when presenting data as predicted values (mean ± 2 SDs) for a given BSA and within equations relating echocardiographic measurements to BSA. Confounders were not included in the final models, because they did not show significant effects for most of the measurements., Conclusions: Echocardiographic reference values are presented for chamber area and diameters, derived from a large population of healthy children. These data partly cover a gap in actual pediatric echocardiographic nomograms. Further studies are required to reinforce these data, as well as to evaluate other parameters and ethnicities., (Copyright © 2014 American Society of Echocardiography. Published by Elsevier Inc. All rights reserved.)

Postsurgical pericardial syndromes are common complications after cardiac surgery; however, their treatment is not well established yet. We reviewed the accuracy and limits of clinical trials of prophylaxis and treatment of these diseases to identify an evidence-based therapeutic approach. We performed a literature search in the National Library of Medicine using the keywords pericardial effusion, cardiac surgery and paediatric/congenital. The research was then redefined adding separately the keywords postpericardiotomy syndrome, NSAIDs, steroids and colchicine. We found 12 clinical trials (eight for the prophylaxis and four regarding treatment), testing three major agent classes: NSAIDs, corticosteroids and colchicine. Therapy is generally based on NSAID with or without steroids with the adjunct of colchicine for recurrences. Only a few randomized controlled trials (RCTs) in adults support NSAID therapy. Efficacy of steroids has been proved only in small paediatric works, whereas no studies are available for colchicine. Studies furthermore presented some limitations: not univocal endpoints (not allowing for a meta-analysis), a limited sample size, scarce attention to confounders (such as the underlying cardiac disease and diuretic/analgesic regimen). Moreover, different agents were not assessed, nor when to start therapy. More evidence (two wide RCT plus a meta-analysis) supports the role of colchicine for prophylaxis in adults. Prophylaxis with NSAID/corticosteroids instead failed to have significant advantage in children, whereas a few data are available for adults. Evidence for the treatment of postsurgical pericardial syndromes is incomplete, making it difficult to understand when to treat and which agent to employ, especially in children.

Background: A quantitative echocardiographic assessment is often essential for the management of congenital heart disease, especially in the first months of life. Despite this, pediatric echocardiographic nomograms are limited and heterogeneous, particularly for neonates and infants. The aim of this study was to establish reliable echocardiographic nomograms in a broad population of healthy Caucasian children., Methods: Two-dimensional and M-mode measurements of 22 cardiovascular structures were performed. Models using linear, logarithmic, exponential, and square root relationships were tested. Heteroscedasticity was tested using the White and Breusch-Pagan tests. Age, weight, height, and body surface area (BSA; calculated using seven different formulas) were used as the independent variables in different analyses to predict the mean value of each echocardiographic measurement. Structured Z scores were then computed., Results: A total of 445 consecutive Caucasian Italian healthy subjects (age range, 0 days to 36 months; 49% female subjects) with BSAs ranging from 0.12 to 0.67 m(2) were prospectively enrolled. The calculation of BSA using the Haycock formula provided the best results, while other formulas either underestimated (DuBois, Mosteller, Dreyer, and Meban) or overestimated (Boyd and Gehan) BSA. The Haycock formula has been used when presenting data as predicted values (mean ± 2 SDs) for a given BSA and within equations relating echocardiographic measurements to BSA. For all the measurements, there was no significant intraobserver or interobserver variability., Conclusions: The investigators report new, reliable echocardiographic Z scores derived from a large population of Caucasian neonates, infants, and toddlers calculated using a rigorous statistical design. These nomograms represent a valid diagnostic tool for echocardiographic quantification in this age group., (Copyright © 2014 American Society of Echocardiography. Published by Mosby, Inc. All rights reserved.)

Background: Percutaneous patent foramen ovale (PFO) closure is accepted as treatment for cryptogenic ischemic stroke/transient ischemic attack in young subjects. However, a thorough evaluation of residual right-to-left shunt (rRLS) after PFO closure is needed. Our aims were to analyze the characteristics related to PFO diagnosis and closure, focusing on rRLS and clinical recurrences until 24-month follow-up. Data were extrapolated from the 12-month Italian PFO Survey., Methods: In all, 1035 patients were included. PFO diagnosis and right-to-left shunt (RLS) were assessed by contrast-enhanced transesophageal and/or transthoracic echocardiography and/or transcranial Doppler., Results: PFO diagnosis with RLS data were available in 894 of 1035 (86.4%) patients. rRLS was investigated in 49.6% (6 months), 27.1% (12 months), and 3.5% (24 months), and observed in 19.5% (6 months) and 18.2% (12 months) of subjects. Large permanent rRLS was observed in less than 3% of RLS-positive patients after 1 year. Eleven of 14 and 3 of 14 neurological recurrences were observed in 10 of 444 (2.25%) and 2 of 243 (0.8%) patients within the 6- and 12-month follow-up, respectively. Among these, no large rRLS was reported. There were no neurological events at 2-year follow-up. Forty of 444 subjects had non-neurological complications, mostly cardiac arrhythmias within the sixth month., Conclusions: PFO closure is a safe procedure. rRLS is not uncommon but large rRLS is rare. Clinical complications, mostly related to cardiac arrhythmias, are not unusual. Evaluation of the data of the whole survey is underway., (Copyright © 2013 National Stroke Association. Published by Elsevier Inc. All rights reserved.)

Introduction and Objectives: To analyze the clinical status of patients with "uncorrected" scimitar syndrome in a multicenter Italian study., Methods: The natural history of scimitar syndrome was analyzed in 44 affected individuals (from 9 Italian centers)., Results: The median age at diagnosis was 1.05 years (range, 1 day-41 years). Thirty-three patients (75%) had an isolated form; 11 patients (25%) had associated congenital heart diseases. Twenty-two patients (50%) were symptomatic at diagnosis, including respiratory symptoms (n=20) and congestive heart failure (n=6). Patients with associated congenital heart defects had a higher prevalence of congestive heart failure (4 of 11 [36.4%] vs 2 of 33 [6.1%]; P=.027), pulmonary arterial hypertension (7 of 11 [63.6%] vs 2 of 33 [6.1%]; P=.027) than patients with isolated forms. Ten patients (22.7%) underwent correction of associated cardiac defects, leaving the anomalous pulmonary venous drainage intact. The median length of follow-up after diagnosis was 6.4 years (range, 0.2-27.5 years). Two patients died, both with associated cardiac defects and severe pulmonary arterial hypertension. Of 42 survivors, 39 (92.8%) were asymptomatic at the last follow-up visit; 3 patients still complained respiratory symptoms. There was no difference between isolated and associated forms of the disease., Conclusions: In most patients, scimitar syndrome presented as an isolated lesion with a benign outcome. Nonetheless, when associated with other cardiac defects and pulmonary arterial hypertension, there was an increased risk of congestive heart failure and mortality. Correction of associated cardiac defects (transforming "associated" into "isolated" forms), together with the therapeutic occlusion of anomalous arterial supply to the lung, led to a benign outcome comparable to that in primarily isolated forms., (Copyright © 2013 Sociedad Española de Cardiología. Published by Elsevier Espana. All rights reserved.)

Background and Aims: Percutaneous implantation of pulmonary valve has been recently introduced in the clinical practice. Our aim was to analyze data of patients treated in Italy by using the Melody Medtronic valve., Methods: Prospective, observational, multi-centric survey by means of a web-based database registry of the Italian Society of Pediatric Cardiology (SICP)., Results: Between October 2007 and October 2010, 63 patients were included in the registry (median age: 24 years; range 11-65 years). Forty subjects were in NYHA class I-II while 23 were in NYHA class III-IV. Patients included had a history of a median three previous surgeries (range 1-5) and a median of one previous cardiac catheterization (range 0-4). A cono-truncal disease was present in 39 patients, previous Ross operation in 9, and other diagnosis in 15. Indication to valve implantation was pure stenosis in 21 patients, pure regurgitation in 12, association of stenosis and regurgitation in 30. Implantation was performed in 61 subjects (97%). Pre-stenting was performed in 85% of cases. Median procedure time was 170 minutes (range 85-360). No significant regurgitation was recorded after procedure while the trans-pulmonary gradient reduced significantly. Early major complications occurred in seven subjects (11%). One death occurred in the early post-operative period in a severely ill subject. At a median follow-up of 30 months (range 12-48 months), three patients died due to underlying disease. Major complications occurred in six patients during follow-up (external electric cardioversion: one patient; herpes virus encephalitis: two patients; Melody valve endocarditis needing surgical explant: two patients; major fractures of the stent and need second Melody valve implantation: two patients). Freedom from valve failure at latest follow-up was 81.4% ± 9%., Conclusion: Early results of the SICP registry on transcatheter Melody pulmonary valve implantation show that the procedure is safe and successful. Major concerns are related to the occurrence of stent fracture and bacterial endocarditis. Longer follow-up and larger series are needed., (Copyright © 2012 Wiley Periodicals, Inc.)

Background: The aim of this study is to test the hypothesis whether the combined use of a cardio-specific biomarker, the brain natriuretic peptide (BNP) and a marker of early renal damage, the assay of urinary neutrophil gelatinase-associated lipocalin (uNGAL), may improve risk stratification in pediatric cardiac surgery., Methods: We prospectively enrolled 135 children [median age 7 (interquartile range 1-49) months] undergoing to cardiac surgery for congenital heart disease. All biomarkers were evaluated pre- and post-operatively at different times after cardiopulmonary-bypass (CPB): uNGAL at 2, 6 and 12 h; BNP at 12 and 36 h; serum creatinine at 2, 6, 12, and 36 h. Primary endpoints were development of acute kidney injury (AKI) (defined as 1.5 serum creatinine increase) and intubation time., Results: AKI occurred in 39% of patients (65% neonates and 32% older children, p=0.004). The peak of uNGAL values occurred more frequently at 2 h. uNGAL values at 2 h [median 28.2 (interquartile range 7.0-124.6) ng/L] had a good diagnostic accuracy for early diagnosis of AKI with an AUC (area under the curve) ROC (receiver operating characteristic) curve of 0.85 (SE 0.034). Using multivariable logistic regression analysis, development of AKI was significantly associated with uNGAL values at 2 h after CPB [OR=1.88 (1.30-2.72, p=0.001)], together with the CPB time and Aristotle score, as an index of complexity of the surgical procedure, while pre-operative BNP values were not. Furthermore, uNGAL and pre-operative BNP values (together with Aristotle score) were significantly associated with adverse outcome (longer intubation time and mortality)., Conclusions: Pre-operative BNP and uNGAL values after surgery (together with the Aristotle score) were independently associated with a more severe course and worse outcome in children undergoing cardiac surgery for congenital heart disease.

Objectives: To evaluate whether the stenting of aortic coarctation enhance the risk of exercise-induced hypertension (EIH)., Background: There is the theoretical concern that aortic stents may cause increased aortic wall impedance and therefore systolic hypertension during exercise., Methods: Blood pressure and the Doppler derived peak and mean systolic pressure gradient (PSG and MSG) across the distal aorta at the peak of exercise were evaluated in young patients (mean age 14 +/- 3 years) with aortic coarctation successfully treated with surgery or with stent implantation at least 1 year before the test. Only patients who reached the 85% maximal predicted heart rate or whose exercise test was interrupted because of severe hypertension, and in whom significant aortic narrowings were excluded by a MRI or a CT scan performed in the six months preceding the exercise test were included in the study., Results: Seventeen patients formed the surgery-group, while 15 patients the stent-group. Patients in surgery-group were younger at coarctation repair and with a longer follow-up than those in stent-group. No difference was present regarding age, body surface area, gender, and presence, and degree of mildly hypoplastic aortic segments between the two groups as well as between patients with or without EIH. EIH was found in 35% of surgery-group patients and in 33% of stent-group patients. PSG and MSG were similar in the patients with or without EIH., Conclusions: EIH can be found in a high number of young patients successfully treated for aortic coarctation but at intermediate follow-up stent implantation does not seem to enhance the risk of EIH.

Background: The seventh Committee on "Biological Effects of Ionizing Radiation" (BEIR VII, 2006) underlines "the need of studies of infants who are exposed to diagnostic radiation because catheters have been placed in their hearts"., Objective: To determine the lifetime attributable risk (LAR) of cancer associated with the estimated cumulative radiological dose in 59 children (42 male, age 2.8+/-3.2 years) with complex congenital heart disease, and to assess chromosomal DNA damage after cardiac catheterisation procedures. Methods In all patients, the cumulative exposure was estimated as effective dose in milliSievert (mSv), and LAR cancer was determined from the BEIR VII report. In a subset of 18 patients (13 male, age 5.2+/-5.7 years) micronucleus as a biomarker of DNA damage and long-term risk predictor of cancer was assayed before and 2 h after catheterisation procedures. Dose-area product (Gy cm(2)) was assessed as a measure of patient dose., Results: The median life time cumulative effective dose was 7.7 mSv per patient (range 4.6-41.2). Cardiac catheterisation procedures and CT were responsible for 95% of the total effective dose. For a 1-year-old child, the LAR cancer was 1 in 382 (25th to 75th centiles: 1 in 531 to 1 in 187) and 1 in 156 (25th to 75th centiles: 1 in 239 to 1 in 83) for male and female patients, respectively. Median micronucleus values increased significantly after the procedure in comparison with baseline (before 6 per thousand vs after 9 per thousand, p=0.02). The median dose-area product value was 20 Gy cm(2) (range 1-277)., Conclusion: Children with congenital heart disease are exposed to a significant cumulative dose. Indirect cancer risk estimations and direct DNA data both emphasise the need for strict radiation dose optimisation in children.

We reported a case of two 24-year-old and 17-year-old male patients with episode of transient ischemic attacks and diagnosed as having patent foramen ovale (PFO). One patient had heterozygosity for the factor V Leiden mutation, and one other had heterozygosity for prothrombin G20210A mutation. Both of them were also carriers for MTHFR 677T genotype with elevated plasma levels of homocysteine (22.3 +/- 3.9 micromol/L). These findings strongly confirm and emphasize the importance of the genetic screening for thrombotic mutations in young patients with PFO-related ischemic events in order to improve secondary prevention strategies.

Aim: To report the experience of 23 tertiary referral European Centres on transcatheter closure of congenital ventricular septal defects (VSD)., Methods and Results: Implantation of transcatheter devices was attempted in 430 patients (pts) with congenital VSDs until July 2005. The following anatomic types were present: 119 muscular, 250 perimembranous, 16 multiple, 45 residual post-surgery. Median VSD size was 7 mm (range 3-22), fluoroscopy time 33 min (range 3-146). Devices implanted were Amplatzer muscular or membranous devices in 364, PDA devices in 12, ASD devices in seven, Starflex in seven, and coils in nine patients. Procedure was successful in 410 cases (95%)., Complications: device embolization in five cases (surgery in two, catheter retrieval in three), aortic regurgitation in 14 cases (two of which requiring surgery), tricuspid regurgitation in 27 cases (no surgery was necessary), minor rhythm disturbances in 10 pts, death in one patient, complete heart block (cAVB) in 16 pts [perimembranous 12 of 250 (5%), muscular one of 119 (0.8%), residual post-surgery VSD three of 45 (6.7%)]. CAVB was transient in six patients, requiring permanent pace-makers in 10 cases (3.8%) (six early, four late). In the multivariate analysis, the only variable associated with a risk of the occurrence of complication was age (P=0.012) and weight (P=0.0035). In the univariate analysis, risk factors for the development of cAVB were, device type (P=0.03) and VSD location (P=0.05). After the multivariable Cox proportional hazards analysis, no risk factor was found., Conclusion: Transcatheter closure of congenital VSDs offers encouraging results. COMPLICATIONS are limited; the most relevant one seems to be the device related to cAVB in perimembranous VSD. More experience and long-term follow-up are mandatory to assess safety and effectiveness of this procedure as an alternative to conventional surgery.

Background and Purpose: Patent foramen ovale (PFO) has been identified as a potential risk factor for cerebrovascular ischemia. Procoagulant mutations may increase the risk and impact the choice of appropriate therapy for secondary prevention. We evaluated the prevalence of the 2 most common genetic risk factors for thromboembolism, factor V Leiden (G1691A) and prothrombin G20210A, in young PFO patients who were referred for percutaneous transcatheter closure of their PFO., Methods: Ninety-seven patients (50 men; mean+/-SD age, 40.9+/-10.0 years) with first-ever cerebrovascular events before the age of 55 years and 160 age-matched control subjects (69 men; mean+/-SD age, 40.4+/-10.5 years) were recruited into the study. Factor V Leiden and prothrombin G20210A mutations were detected by using a multiplex allele-specific polymerase chain reaction assay., Results: The prevalence of subjects carrying at least 1 prothrombotic genotype was significantly higher in the group of PFO patients than in the group of controls (10.3% vs 2.5%; chi(2)=7.2, P=0.008). Two patients (2.1%) versus 1 control subject (0.6%) and 8 cases (8.2%) versus 3 controls (1.9%) were carriers for factor V Leiden and prothrombin G20210A mutations, respectively. After adjustment for other vascular risk factors, the combination of either factor V Leiden or prothrombin G20210A and PFO was associated with a 4.7-fold (95% CI=1.4 to 16.1; P=0.008) increased risk of cerebral ischemia in young patients., Conclusions: Our results indicate that prothrombotic mutations are important risk factors for cerebral ischemia in young patients with PFO. Screening for thrombotic mutations should be considered in young patients with PFO-related ischemic events.

After lung surgery, some patients complain of unexplained increased dyspnoea associated with hypoxaemia. This clinical presentation may be due to an interatrial right-to-left shunt despite normal right heart pressure. Some of these patients show postural dependency of hypoxaemia, whereas others do not. In this article, the pathogenesis and mechanisms involved in this post-surgical complication are discussed, and the techniques used for confirmation and localisation of shunt are reported. An invasive technique, such as right heart catheterisation with angiography, was often used in the past as the diagnostic procedure for the visualisation of interatrial shunt. As to noninvasive techniques, a perfusion lung scan may be used as the first approach as it may detect the effect of the right-to-left shunt by visualising an extrapulmonary distribution of the radioactive tracer. The 100% oxygen breathing test could also be used to quantify the amount of right-to-left shunt. Particular emphasis is given to newer imaging modalities, such as transoesophageal echocardiography, which is minimally invasive but highly sensitive in clearly visualising the atrial septum anatomy. Finally, the approach to closure of the foramen ovale or atrial septal defect is discussed. Open thoracotomy was the traditional approach in the past. Percutaneous closure has now become the most used and effective technique for the repair of the interatrial anatomical malformation.

Haploinsufficiency of chromosome 22q11.2 is a well-established cause of both the DiGeorge anomaly and the velocardiofacial syndrome. This condition shows a continuous spectrum of phenotypic manifestations with a considerable inter- and intrafamilial variability. We report on a three-generation family with four members sharing the same 3 Mb long deletion but showing different phenotypic expression. In the first generation, the deleted patient has hypernasal speech and suffers from recurrent psychotic episodes. Two of her offspring inherited the deletion. One of these, a male, has hypernasal speech, low-set ears, hypocalcemia, severe development delay, and tetralogy of Fallot. The other, a female, has hypernasal speech, minor facial anomalies, and very mild mental retardation. Her daughter has tetralogy of Fallot, velopharyngeal insufficiency, and mild facial anomalies. This family is an example of the widely variable phenotypic expressivity of the 22q11.2 deletion. There is no correlation between the size of the deletion and the phenotypic manifestations. Genetic background and/or environmental factors could explain the different phenotypes observed in the affected members of the family., (Copyright 2002 Wiley-Liss, Inc.)

In recent years, percutaneous placement of stents has been used as an alternative to surgery or balloon angioplasty for the treatment of adults with peripheral pulmonary arterial stenosis. This therapy has also been proposed for children, but questions still remain about its indications in this group of patients. We describe here the results of intravascular placement of stents in a group of 29 patients, with a mean age of 12+/-7 (range 3-31) years and weighing 35+/-19 (range 11-74) kg. All were affected by postsurgical or congenital isolated pulmonary arterial stenosis, and have now been followed for 38+/-19 (range 6-65) months. The early hemodynamic results have been excellent, with a significant reduction of the pulmonary arterial systolic pressure, the systolic pressure gradient, and the ratio of systolic pressures in the pulmonary and systemic circuits, and with a significant increase of the diameter of the stented vessels in all the patients. Of the 29 patients, 24 have been recatheterized 18+/-10 months after the procedure, demonstrating the stability of the results, with a low incidence of late restenosis, this seen in only 1 patient (2%). Lung perfusion scanning, performed in 17 patients each year after the follow-up catheterization, has showed that the results are maintained at long-term follow-up (51+/-9 months).

Methods: Four neonates with Pulmonary Atresia and intact Ventricular Septum underwent Radiofrequency Valvotomy in our institution from October 1994 to June 1995. All patients had "membranous" atresia with confluent and normal size pulmonary branches; one of them had abnormal tricuspid tensor apparatus and severe right ventricular outflow tract hypertrophy. The right ventricle was considered of sufficient size to support biventricular circulation in all cases. In three patients the pulmonary arteries were supplied by the arterial duct maintained open with intravenous infusion of Prostaglandins. The other patient had previously undergone a modified left Blalock Taussig shunt in another institution. The cardiac catheterization was performed by the femoral venous and arterial routes, under general anesthesia. After delineating the atretic valve with angiography, a 5 French right Judkins catheter was placed in the right ventricular outflow tract just beneath the membrane. A 2 french radiofrequency catheter (Cerablate PA 120 Osypka) was then passed through the right Judkins; with a mean energy of 5-10 watts over 3-5 seconds the valve was perforated. After a predilation with a 2,5 mm balloon catheter (New Probe USCI or Cobra SCIMED), the valve was dilated with balloon catheters 20 to 30% larger than the anulus (Cristal Balloon BALT)., Results: In all cases the procedure was successful without any complication; a significant decrease of right ventricular pressure and an excellent antegrade flow across the valve were achieved. Two patients were weaned from prostaglandins by sixth and eighth day after the procedure. The patient with previous Bialock Taussig shunt showed a complete recovery of the right ventricle, but four months later underwent surgery for shunt closure and enlargement of the left pulmonary branch. These three patients are well at latest follow-up (5-10 months), with normal biventricular circulation. The other patient remained duct-dependent and was operated on of outflow patch and shunt nine days after the procedure, with good result; he unfortunately died the tenth postoperative day for complications of hemopericardium related to epicardial wires removal., Conclusions: In our opinion radiofrequency valvotomy is the first choice procedure in cases suitable for biventricular repair. In selected patients it may represent a definitive treatment.

The aim of this study was to present the experience of 2 Institutions (Department of Cardiology in Bergamo and Department of Pediatric Cardiology, Apuano Pediatric Hospital in Massa) in performing the balloon dilatation of the pulmonary valve. From January 1985 to August 1993 the balloon pulmonary valvuloplasty was performed in 220 patients, age ranging from 1 day to 60 years (mean age 5 years), 55 (25%) in the first year of life, 17 (8%) in the first week of life. The systolic gradient across the pulmonary valve fell from 78 +/- 31 mmHg (range 40-160) to 20 +/- 16 mmHg (range 0-70) immediately after the procedure (p < 0.001). In-hospital mortality happened in 3 cases (1.3%); 2 of them were neonates with critical pulmonary stenosis. In 7 cases (3%) the balloon valvuloplasty was repeated afterwards, because of inadequate relief of the gradient after the first dilatation. During the mean follow-up period of 4 years the other 210 patients (95%) did not need any further treatment and remain in stable clinical conditions. The balloon valvuloplasty gives excellent early and intermediate term results and should be considered the first choice procedure in the treatment of pulmonary stenosis at all ages.

Four patients of 5, 27, 27 and 62 years of age, who previously underwent surgical ligation of ductus arteriosus (respectively 3, 17, 19 and 17 years before), came to our observation because of recanalization of the duct. In three cases the duct was an isolated finding, whereas in the oldest patient the duct ligation had been accompanied by implantation of a Starr prosthesis in aortic position. The diagnosis of residual shunt was based on the auscultation of a continuous murmur at the left subclavicular space and on typical signs of patent ductus evidenced by Doppler interrogation. In all cases the diagnosis was confirmed by angiography; the minimal diameter of the ducts varied between 2.5 and 4 mm. Three umbrellas of 17 mm and one of 12 mm diameter were employed for the closure of the residual shunt. The implantation of the double-umbrella device was obtained with the routine transfemoral venous approach. In the youngest patient, in order to facilitate the progression of the transseptal catheter through the duct, it was necessary to create a circuit with the guide wire from the femoral vein to the contralateral femoral artery. In all four patients the shunt was completely abolished. The oldest patient underwent replacement of a malfunctioning aortic prosthesis three days after implantation of the double-umbrella device; the surgical approach was this way significantly simplified. The implantation of a Rashkind double-umbrella device is the method of choice for closure of residual shunts through the duct after surgical ligation.

Many cases of fistulae between coronary arteries and heart chambers are now detectable because of improvement in selective coronary artery angiography. Coronary fistulae may be congenital or secondary to cardiac disease such as atrial tumors, mitral stenosis with atrial thrombosis or ventricular aneurysm. A case of a patient with rheumatic heart disease and multiple fistulae between coronary arteries and left atrium, is reported. A thin mural thrombus adherent to the left atrial wall, unsuspected preoperatively, was discovered at surgery and gave the clue to the pathological origin of the fistulae.