Giovanni Stellin

Modulation of microRNA expression in human T-cell development: targeting of NOTCH3 by miR-150.

Ontogenesis of T cells in the thymus is a complex process whose molecular control is poorly understood. The present study investigated microRNAs involved in human thymocyte differentiation by comparing the microRNA expression profiles of thymocytes at the double-positive, single-positive CD4(+) and single-positive CD8(+) maturation stages. Microarray analysis showed that each thymocyte population displays a distinct microRNA expression profile that reflects their developmental relationships. Moreover, analysis of small-RNA libraries generated from human unsorted and double-positive thymocytes and from mature peripheral CD4(+) and CD8(+) T lymphocytes, together with the microarray data, indicated a trend toward up-regulation of microRNA expression during T-cell maturation after the double-positive stage and revealed a group of microRNAs regulated during normal T-cell development, including miR-150, which is strongly up-regulated as maturation progresses. We showed that miR-150 targets NOTCH3, a member of the Notch receptor family that plays important roles both in T-cell differentiation and leukemogenesis. Forced expression of miR-150 reduces NOTCH3 levels in T-cell lines and has adverse effects on their proliferation and survival. Overall, these findings suggest that control of the Notch pathway through miR-150 may have an important impact on T-cell development and physiology.

The nomenclature, definition and classification of hypoplastic left heart syndrome

The hypoplastic left heart syndrome encompasses a spectrum of cardiac malformations that are characterized by significant underdevelopment of the components of the left heart and the aorta, including the left ventricular cavity and mass. At the severe end of the spectrum is found the combination of aortic and mitral atresia, when the left ventricle can be close to non-existent. At the mild end are the patients with hypoplasia of the aortic and mitral valves, but without intrinsic valvar stenosis or atresia, and milder degrees of left ventricular hypoplasia. Although the majority of the patients are suitable only for functionally univentricular repair, a small minority may be candidates for biventricular repair. The nature of the syndrome was a topic for discussion at the second meeting of the International Working Group for Mapping and Coding of Nomenclatures for Paediatric and Congenital Heart Disease, the Nomenclature Working Group, held in Montreal, Canada, over the period January 17 through 19, 2003. Subsequent to these discussions, the Nomenclature Working Group was able to create a bidirectional crossmap between the nomenclature initially produced jointly on behalf of the European Association for Cardio-Thoracic Surgery and the Society of Thoracic Surgeons, and the alternative nomenclature developed on behalf of the Association for European Paediatric Cardiology. This process is a part of the overall efforts of the Nomenclature Working Group to create a comprehensive and all-inclusive international system of nomenclature for paediatric and congenital cardiac disease, the International Paediatric and Congenital Cardiac Code. In this review, we discuss the evolution of nomenclature and surgical treatment for the spectrum of lesions making up the hypoplastic left heart syndrome and its related malformations. We also present the crossmap of the associated terms for diagnoses and procedures, as recently completed by the Nomenclature Working Group.

Liver and Cardiac Function in the Long Term After Fontan Operation

BACKGROUND Patients who underwent Fontan operation have some degree of liver disease. We aimed to assess the long-term liver and cardiac function after Fontan operation. METHODS Patients enrolled underwent physical examination, biochemical tests (aspartate aminotransferase, alanine aminotransferase, gamma glutamyl transpeptidase, bilirubin, international normalized ratio, coagulation factor V, protein profile, fecal alpha-1-antitrypsin), echocardiogram, and liver ultrasonography. A liver disease score was adopted to compare the degree of liver involvement with hemodynamic features. RESULTS The study enrolled 34 patients, median age 14.7 years (range, 4.1 to 26.7), 26 with a residual left ventricle, 8 with a residual right ventricle, affected by tricuspid atresia (17), pulmonary atresia (4), hypoplastic left heart syndrome (5), double-outlet right ventricle (2), single left ventricle (2), and miscellaneous (4), with median follow-up of 11.5 years (range, 1.7 to 23.3). We found hepatomegaly in 18 of 34 (53%), splenomegaly in 3 of 33 (9%), abnormal transaminases in 10 of 33 (30%), elevated gamma GT in 19 of 31 (61%), elevated bilirubin in 10 of 31 (32%), coagulopathy in 17 of 29 (58%), and protein-losing enteropathy in 4 of 21 (19%). Median heart rate z-score was -1.72. Hepatic dysfunction was strictly correlated to low cardiac index (r(2) = 0.34, p = 0.008) and to a lesser extent to reduced heart rate (r(2) = 0.18, p = 0.07). CONCLUSIONS In children who underwent Fontan operation, hepatic dysfunction is correlated with low cardiac index and reduced heart rate. Maintaining or reestablishing a normal cardiac index might prevent or reduce liver disease in the long-term.

Scimitar Syndrome A European Congenital Heart Surgeons Association (ECHSA) Multicentric Study

Background— Scimitar syndrome is a rare congenital heart disease. To evaluate the surgical results, we embarked on the European Congenital Heart Surgeons Association (ECHSA) multicentric study. Methods and Results— From January 1997 to December 2007, we collected data on 68 patients who underwent surgery for scimitar syndrome. Primary outcomes included hospital mortality and the efficacy of repair at follow-up. Median age at surgery was 1.4 years (interquartile range, 0.46 to 7.92 years). Forty-four patients (64%) presented with symptoms. Surgical repair included intraatrial baffle in 38 patients (56%; group 1) and reimplantation of the scimitar vein onto the left atrium in 21 patients (31%; group 2). Eight patients underwent right pneumectomy, and 1 had a right lower lobe lobectomy (group 3). Four patients died in hospital (5.9%; 1 patient in group 1, 2.6%; 3 patients in group 3, 33%). Median follow-up time was 4.5 years. There were 2 late deaths (3.1%) resulting from severe pulmonary arterial hypertension. Freedom from scimitar drainage stenosis at 13 years was 83.8% in group 1 and 85.8% in group 2. Four patients in group 1 were reoperated, and 3 patients (2 in group 1 [6%] and 1 in group 2 [4.8%]) required balloon dilation/stenting for scimitar drainage stenosis. Conclusions— The surgical treatment of this rare syndrome is safe and effective. The majority of patients were asymptomatic at the follow-up control. There were a relatively high incidence of residual scimitar drainage stenosis that is similar between the 2 reported corrective surgical techniques used. # Clinical Perspective {#article-title-44}Background— Scimitar syndrome is a rare congenital heart disease. To evaluate the surgical results, we embarked on the European Congenital Heart Surgeons Association (ECHSA) multicentric study. Methods and Results— From January 1997 to December 2007, we collected data on 68 patients who underwent surgery for scimitar syndrome. Primary outcomes included hospital mortality and the efficacy of repair at follow-up. Median age at surgery was 1.4 years (interquartile range, 0.46 to 7.92 years). Forty-four patients (64%) presented with symptoms. Surgical repair included intraatrial baffle in 38 patients (56%; group 1) and reimplantation of the scimitar vein onto the left atrium in 21 patients (31%; group 2). Eight patients underwent right pneumectomy, and 1 had a right lower lobe lobectomy (group 3). Four patients died in hospital (5.9%; 1 patient in group 1, 2.6%; 3 patients in group 3, 33%). Median follow-up time was 4.5 years. There were 2 late deaths (3.1%) resulting from severe pulmonary arterial hypertension. Freedom from scimitar drainage stenosis at 13 years was 83.8% in group 1 and 85.8% in group 2. Four patients in group 1 were reoperated, and 3 patients (2 in group 1 [6%] and 1 in group 2 [4.8%]) required balloon dilation/stenting for scimitar drainage stenosis. Conclusions— The surgical treatment of this rare syndrome is safe and effective. The majority of patients were asymptomatic at the follow-up control. There were a relatively high incidence of residual scimitar drainage stenosis that is similar between the 2 reported corrective surgical techniques used.

Nomenclature and databases for the surgical treatment of congenital cardiac disease - an updated primer and an analysis of opportunities for improvement

This review discusses the historical aspects, current state of the art, and potential future advances in the areas of nomenclature and databases for the analysis of outcomes of treatments for patients with congenitally malformed hearts. We will consider the current state of analysis of outcomes, lay out some principles which might make it possible to achieve life-long monitoring and follow-up using our databases, and describe the next steps those involved in the care of these patients need to take in order to achieve these objectives. In order to perform meaningful multi-institutional analyses, we suggest that any database must incorporate the following six essential elements: use of a common language and nomenclature, use of an established uniform core dataset for collection of information, incorporation of a mechanism of evaluating case complexity, availability of a mechanism to assure and verify the completeness and accuracy of the data collected, collaboration between medical and surgical subspecialties, and standardised protocols for life-long follow-up. During the 1990s, both The European Association for Cardio-Thoracic Surgery and The Society of Thoracic Surgeons created databases to assess the outcomes of congenital cardiac surgery. Beginning in 1998, these two organizations collaborated to create the International Congenital Heart Surgery Nomenclature and Database Project. By 2000, a common nomenclature, along with a common core minimal dataset, were adopted by The European Association for Cardio-Thoracic Surgery and The Society of Thoracic Surgeons, and published in the Annals of Thoracic Surgery. In 2000, The International Nomenclature Committee for Pediatric and Congenital Heart Disease was established. This committee eventually evolved into the International Society for Nomenclature of Paediatric and Congenital Heart Disease. The working component of this international nomenclature society has been The International Working Group for Mapping and Coding of Nomenclatures for Paediatric and Congenital Heart Disease, also known as the Nomenclature Working Group. By 2005, the Nomenclature Working Group crossmapped the nomenclature of the International Congenital Heart Surgery Nomenclature and Database Project of The European Association for Cardio-Thoracic Surgery and The Society of Thoracic Surgeons with the European Paediatric Cardiac Code of the Association for European Paediatric Cardiology, and therefore created the International Paediatric and Congenital Cardiac Code, which is available for free download from the internet at [http://www.IPCCC.NET]. This common nomenclature, the International Paediatric and Congenital Cardiac Code, and the common minimum database data set created by the International Congenital Heart Surgery Nomenclature and Database Project, are now utilized by both The European Association for Cardio-Thoracic Surgery and The Society of Thoracic Surgeons. Between 1998 and 2007 inclusive, this nomenclature and database was used by both of these two organizations to analyze outcomes of over 150,000 operations involving patients undergoing surgical treatment for congenital cardiac disease. Two major multi-institutional efforts that have attempted to measure the complexity of congenital heart surgery are the Risk Adjustment in Congenital Heart Surgery-1 system, and the Aristotle Complexity Score. Current efforts to unify the Risk Adjustment in Congenital Heart Surgery-1 system and the Aristotle Complexity Score are in their early stages, but encouraging. Collaborative efforts involving The European Association for Cardio-Thoracic Surgery and The Society of Thoracic Surgeons are under way to develop mechanisms to verify the completeness and accuracy of the data in the databases. Under the leadership of The MultiSocietal Database Committee for Pediatric and Congenital Heart Disease, further collaborative efforts are ongoing between congenital and paediatric cardiac surgeons and other subspecialties, including paediatric cardiac anaesthesiologists, via The Congenital Cardiac Anesthesia Society, paediatric cardiac intensivists, via The Pediatric Cardiac Intensive Care Society, and paediatric cardiologists, via the Joint Council on Congenital Heart Disease and The Association for European Paediatric Cardiology. In finalizing our review, we emphasise that analysis of outcomes must move beyond mortality, and encompass longer term follow-up, including cardiac and non cardiac morbidities, and importantly, those morbidities impacting health related quality of life. Methodologies must be implemented in these databases to allow uniform, protocol driven, and meaningful, long term follow-up.

Repair of tetralogy of Fallot in the first six months of life: Transatrial versus transventricular approach

BACKGROUND This report describes our experience with primary correction of tetralogy of Fallot in infants. METHODS Fifty-one consecutive infants younger than 6 months underwent primary correction of tetralogy of Fallot between January 1978 and October 1994. Mean age at repair was 4.2 months. Four were neonates. Correction was accomplished through a right ventriculotomy in the first consecutive 22 patients (43%; group A); since 1991, a combined transatrial-transpulmonary approach was used in 29 consecutive patients (57%; group B). A transannular patch was necessary in 33 infants (65%) 16 of group A (73%) and 17 of group B (59%). RESULTS There was one early death from possible left anterior descending coronary artery distortion in group A and no deaths in group B. Two patients required early reoperation for systemic-to-pulmonary artery collateral ligation (postoperative day 6) and permanent pacemaker implantation (postoperative day 30). There were no late deaths. All 50 survivors are currently asymptomatic and in New York Heart Association class I. Three patients required late reoperations 36 months, 30 months, and 13 months after repair for (1) subaortic stenosis and dysfunctioning dysplastic mitral valve, (2) residual pulmonary artery branch stenosis, and (3) residual right ventricular outflow obstruction. Four patients underwent balloon dilation and stent insertion (1 patient) for peripheral pulmonary artery stenosis 1.5 year to 12 years (mean, 5 years) after initial repair. Actuarial freedom from need for reintervention at 4 years was 78.4% in group A and 85.7% in group B. Two-dimensional and Doppler echocardiographic follow-up studies showed a residual mild to moderate pulmonary artery branch stenosis in 4 patients in group A, and a recurrent subaortic stenosis in 1 patient in group A. Right ventricular peak systolic pressure was less than 40 mm hg in all but 3 asymptomatic patients who had a residual pulmonary artery branch stenosis. Right ventricular end-systolic and end-diastolic volumes showed larger volumes and reduced ejection fraction in group A compared with group B. CONCLUSIONS This limited experience with repair of tetralogy of Fallot in patients less than 6 months of age demonstrates that the transatrial-transventricular approach is possible in neonates and young infants with a very low mortality and morbidity and also a low incidence of residual lesions. Follow-up echocardiographic data suggest that right ventricular function is better preserved in those patients who underwent the transatrial-transpulmonary repair.

The improvement of care for paediatric and congenital cardiac disease across the World: a challenge for the World Society for Pediatric and Congenital Heart Surgery

The diagnosis and treatment for paediatric and congenital cardiac disease has undergone remarkable progress over the last 60 years. Unfortunately, this progress has been largely limited to the developed world. Yet every year approximately 90% of the more than 1,000,000 children who are born with congenital cardiac disease across the world receive either suboptimal care or are totally denied care.While in the developed world the focus has changed from an effort to decrease post-operative mortality to now improving quality of life and decreasing morbidity, which is the focus of this Supplement, the rest of the world still needs to develop basic access to congenital cardiac care. The World Society for Pediatric and Congenital Heart Surgery [http://www.wspchs.org/] was established in 2006. The Vision of the World Society is that every child born anywhere in the world with a congenital heart defect should have access to appropriate medical and surgical care. The Mission of the World Society is to promote the highest quality comprehensive care to all patients with pediatric and/or congenital heart disease, from the fetus to the adult, regardless of the patients economic means, with emphasis on excellence in education, research and community service.We present in this article an overview of the epidemiology of congenital cardiac disease, the current and future challenges to improve care in the developed and developing world, the impact of the globalization of cardiac surgery, and the role that the World Society should play. The World Society for Pediatric and Congenital Heart Surgery is in a unique position to influence and truly improve the global care of children and adults with congenital cardiac disease throughout the world [http://www.wspchs.org/].

Initial application in the EACTS and STS Congenital Heart Surgery Databases of an empirically derived methodology of complexity adjustment to evaluate surgical case mix and results

OBJECTIVES Outcomes evaluation is enhanced by assignment of operative procedures to appropriate categories based upon relative average risk. Formal risk modelling is challenging when a large number of operation types exist, including relatively rare procedures. Complexity stratification provides an alternative methodology. We report the initial application in the Congenital Heart Surgery Databases of the Society of Thoracic Surgeons (STS) and the European Association for Cardio-thoracic Surgery (EACTS) of an empirically derived system of complexity adjustment to evaluate surgical case mix and results. METHODS Complexity stratification is a method of analysis in which the data are divided into relatively homogeneous groups (called strata). A complexity stratification tool named the STS-EACTS Congenital Heart Surgery Mortality Categories (STAT Mortality Categories) was previously developed based on the analysis of 77,294 operations entered in the Congenital Heart Surgery Databases of EACTS (33,360 operations) and STS (43,934 patients). Procedure-specific mortality rate estimates were calculated using a Bayesian model that adjusted for small denominators. Operations were sorted by increasing risk and grouped into five categories (the STAT Mortality Categories) that were designed to minimize within-category variation and maximize between-category variation. We report here the initial application of this methodology in the EACTS Congenital Heart Surgery Database (47,187 operations performed over 4 years: 2006-09) and the STS Congenital Heart Surgery Database (64,307 operations performed over 4 years: 2006-09). RESULTS In the STS Congenital Heart Surgery Database, operations classified as STAT Mortality Categories 1-5 were (1): 17332, (2): 20114, (3): 9494, (4): 14525 and (5): 2842. Discharge mortality was (1): 0.54%, (2): 1.6%, (3): 2.4%, (4): 7.5% and (5): 17.8%. In the EACTS Congenital Heart Surgery Database, operations classified as STAT Mortality Categories 1-5 were (1): 19874, (2): 12196, (3): 5614, (4): 8287 and (5): 1216. Discharge mortality was (1): 0.99%, (2): 2.9%, (3): 5.0%, (4): 10.3% and (5): 25.0%. CONCLUSIONS The STAT Mortality Categories facilitate analysis of outcomes across the wide spectrum of distinct congenital heart surgery operations including infrequently performed procedures.

Surgery for complications of trans-catheter closure of atrial septal defects: a multi-institutional study from the European Congenital Heart Surgeons Association

OBJECTIVE This study aims to analyse the collective experience of participating European Congenital Heart Surgeons Association centres in the surgical management of complications resulting from trans-catheter closure of atrial septal defects (ASDs). METHODS The records of all (n=56) patients, aged 3-70 years (median 18 years), who underwent surgery for complications of trans-catheter ASD closure in 19 participating institutions over a 10-year period (1997-2007) were retrospectively reviewed. Risk factors for surgical complications were sought. Surgical outcomes were compared with those reported for primary surgical ASD closure in the European Association of Cardio-thoracic Surgery Congenital Database. RESULTS A wide range of ASD sizes (5-34mm) and devices of various types and sizes (range 12-60mm) were involved, including 13 devices less than 20mm. Complications leading to surgery included embolisation (n=29), thrombosis/thrombo-embolism/cerebral ischaemia or stroke (n=12), significant residual shunt (n=12), aortic or atrial perforation or erosion (n=9), haemopericardium with tamponade (n=5), aortic or mitral valve injury (n=2) and endocarditis (n=1). Surgery (39 early emergent and 17 late operations) involved device removal, repair of damaged structures and ASD closure. Late operations were needed 12 days to 8 years (median 3 years) after device implantation. There were three hospital deaths (mortality 5.4%). During the same time period, mortality for all 4453 surgical ASD closures reported in the European Association of Cardio-Thoracic Surgery Congenital Database was 0.36% (p=0.001). CONCLUSIONS Trans-catheter device closure of ASDs, even in cases when small devices are used, can lead to significant complications requiring surgical intervention. Once a complication leading to surgery occurs, mortality is significantly greater than that of primary surgical ASD closure. Major complications can occur late after device placement. Therefore, lifelong follow-up of patients in whom ASDs have been closed by devices is mandatory.

Nomenclature and databases - The past, the present, and the future: A primer for the congenital heart surgeon

This review discusses the historical aspects, current state of the art, and potential future advances in the areas of nomenclature and databases for congenital heart disease. Five areas will be reviewed: (1) common language = nomenclature, (2) mechanism of data collection (database or registry) with an established uniform core data set, (3) mechanism of evaluating case complexity, (4) mechanism to ensure and verify data completeness and accuracy, and (5) collaboration between medical subspecialties.During the 1990s, both the Society of Thoracic Surgeons (STS) and the European Association for Cardiothoracic Surgery (EACTS) created congenital heart surgery outcomes databases. Beginning in 1998, the EACTS and STS collaborated in the work of the International Congenital Heart Surgery Nomenclature and Database Project. By 2000, a common congenital heart surgery nomenclature, along with a common core minimal data set, were adopted by the EACTS and the STS and published in the Annals of Thoracic Surgery. In 2000, the International Nomenclature Committee for Pediatric and Congenital Heart Disease was established; this committee eventually evolved into the International Society for Nomenclature of Paediatric and Congenital Heart Disease (ISNPCHD). The working component of ISNPCHD is the International Working Group for Mapping and Coding of Nomenclatures for Paediatric and Congenital Heart Disease, also known as the Nomenclature Working Group (NWG). By 2005, the NWG cross-mapped the EACTS–STS nomenclature with the European Paediatric Cardiac Code of the Association for European Paediatric Cardiology and created the International Paediatric and Congenital Cardiac Code (IPCCC) (http://www.IPCCC.NET).This common nomenclature (IPCCC), and the common minimum database data set created by the International Congenital Heart Surgery Nomenclature and Database Project, are now utilized by both EACTS and STS; since 1998, this nomenclature and database have been used by both the STS and EACTS to analyze outcomes of more than 75,000 patients. Two major multi-institutional efforts have attempted to measure case complexity; the Risk Adjustment in Congenital Heart Surgery-1 and the Aristotle Complexity Score. Efforts to unify these two scoring systems are in their early stages but are encouraging. Collaborative efforts involving the EACTS and STS are under way to develop mechanisms to verify data completeness and accuracy. Further collaborative efforts are also ongoing between pediatric and congenital heart surgeons and other subspecialties, including pediatric cardiac anesthesiologists (via the Congenital Cardiac Anesthesia Society), pediatric cardiac intensivists (via the Pediatric Cardiac Intensive Care Society), and pediatric cardiologists (via the Joint Council on Congenital Heart Disease). Clearly, methods of congenital heart disease outcomes analysis continue to evolve, with continued advances in five areas: nomenclature, database, complexity adjustment, data verification, and subspecialty collaboration.