NKX2-5 regulates the expression of beta-catenin and GATA4 in ventricular myocytes.

BackgroundThe molecular pathway that controls cardiogenesis is temporally and spatially regulated by master transcriptional regulators such as NKX2-5, Isl1, MEF2C, GATA4, and beta-catenin. The interplay between these factors and their downstream targets are not completely understood. Here, we studied regulation of beta-catenin and GATA4 by NKX2-5 in human fetal cardiac myocytes.Methodology/principal findingsUsing antisense inhibition we disrupted the expression of NKX2-5 and studied changes in expression of cardiac-associated genes. Down-regulation of NKX2-5 resulted in increased beta-catenin while GATA4 was decreased. We demonstrated that this regulation was conferred by binding of NKX2-5 to specific elements (NKEs) in the promoter region of the beta-catenin and GATA4 genes. Using promoter-luciferase reporter assay combined with mutational analysis of the NKEs we demonstrated that the identified NKX2-5 binding sites were essential for the suppression of beta-catenin, and upregulation of GATA4 by NKX2-5.ConclusionsThis study suggests that NKX2-5 modulates the beta-catenin and GATA4 transcriptional activities in developing human cardiac myocytes

Subaortic stenosis in the spectrum of atrioventricular septal defects Solutions may be complex and palliative

AbstractFrom July 1982 through September 1994, 19 children had operative treatment of subaortic stenosis associated with an atrioventricular septal defect. Specific diagnosis were septum primum defects in 7, Rastelli type A defects in 6, transitional defects in 4, inlet ventricular septal defect with malattached chordae in 1, and tetralogy of Fallot with Rastelli type C defect in 1. Twenty-seven operations for subaortic stenosis were performed. Surgical treatment of the outlet lesion was performed at initial atrioventricular septal defect repair in 3 children and in the remaining 16 from 1.2 to 13.1 years (mean 4.9 years, median 3.9 years) after repair. Eighteen of the 19 children had fibrous resection and myectomy for relief of obstruction. Seven children had an associated left atrioventricular valve procedure. One child received an apicoaortic conduit. Seven children (36.8%) required 8 reoperations for previously treated subaortic stenosis. Time to the second procedure was 2.8 to 7.4 years (mean 4.9 years). Follow-up is 0.4 to 14.0 years (median 5.6 years). Six-year actuarial freedom from reoperation is 66% ±15%. The angle between the plane of the outlet septum and the plane of the septal crest was measured in 10 normal hearts (86.4 ±13.7) and 10 hearts with atrioventricular septal defects (22.2 ±26.0; p <0.01). The outflow tract can be effectively shortened, widened, and the angle increased toward normal by augmenting the left side of the superior bridging leaflet and performing a fibromyectomy. Conclusion: Standard fibromyectomy for subaortic stenosis in children with atrioventricular septal defects leads to a high rate of reoperation. Leaflet augmentation and fibromyectomy may decrease the likelihood of reoperation. (J THORAC CARDIOVASC SURG 1995;110:1534-42

Persistent fenestration may be a marker for physiologic intolerance after Fontan completion

BackgroundWe sought to evaluate the medium-term implications of fenestration status.MethodsBetween 1994 and 2012, 326 patients received an extracardiac Fontan (hospital mortality n = 6, 1.8%). A fenestration was routinely created (n = 306, 94%) unless there was technical difficulty. Three hundred patients discharged with an open fenestration were included. The primary end points were death and Fontan failure. Secondary outcomes were Fontan complications such as venovenous collaterals, protein-losing enteropathy, pacemaker requirement, and arrhythmias.ResultsThe fenestration was closed in 260 patients: 185 as a catheter intervention (62%) and 75 (25%) spontaneously. Forty patients (13%) had the fenestration open at a median follow-up period of 5.05 years. Of these patients, catheter-based closure failed in 10 (3%). There was no statistically significant difference in pre-Fontan hemodynamic parameters, such as pulmonary artery pressure and pulmonary vascular resistance between the patients with open fenestration and the ones with closed fenestration. Patients with an open fenestration had significantly more late deaths (P < .001), Fontan failure (P = .021), and Fontan complications (P = .011) compared with those with a closed fenestration. Multivariable Cox regression revealed open fenestration (P < .001) and indeterminate ventricular morphology (P = .002) as risk factors for death/Fontan failure, and ventricular dysfunction (P = .014) and open fenestration (P = .009) as risk factors for Fontan complications.ConclusionsPersistent fenestration was a marker for physiologic intolerance as noted by increased rates of mortality and a higher incidence of Fontan failure/complications. The specificity of pre-Fontan physiologic data for fenestration status may not have the fidelity needed for long-term care and thus, the consequences of decision making regarding fenestration status may not be determined until well after the operation

Case complexity scores in congenital heart surgery: A comparative study of the Aristotle Basic Complexity score and the Risk Adjustment in Congenital Heart Surgery (RACHS-1) system

ObjectiveThe Aristotle Basic Complexity score and the Risk Adjustment in Congenital Heart Surgery system were developed by consensus to compare outcomes of congenital cardiac surgery. We compared the predictive value of the 2 systems.MethodsOf all index congenital cardiac operations at our institution from 1982 to 2004 (n = 13,675), we were able to assign an Aristotle Basic Complexity score, a Risk Adjustment in Congenital Heart Surgery score, and both scores to 13,138 (96%), 11,533 (84%), and 11,438 (84%) operations, respectively. Models of in-hospital mortality and length of stay were generated for Aristotle Basic Complexity and Risk Adjustment in Congenital Heart Surgery using an identical data set in which both Aristotle Basic Complexity and Risk Adjustment in Congenital Heart Surgery scores were assigned. The likelihood ratio test for nested models and paired concordance statistics were used.ResultsAfter adjustment for year of operation, the odds ratios for Aristotle Basic Complexity score 3 versus 6, 9 versus 6, 12 versus 6, and 15 versus 6 were 0.29, 2.22, 7.62, and 26.54 (P < .0001). Similarly, odds ratios for Risk Adjustment in Congenital Heart Surgery categories 1 versus 2, 3 versus 2, 4 versus 2, and 5/6 versus 2 were 0.23, 1.98, 5.80, and 20.71 (P < .0001). Risk Adjustment in Congenital Heart Surgery added significant predictive value over Aristotle Basic Complexity (likelihood ratio χ2 = 162, P < .0001), whereas Aristotle Basic Complexity contributed much less predictive value over Risk Adjustment in Congenital Heart Surgery (likelihood ratio χ2 = 13.4, P = .009). Neither system fully adjusted for the child’s age. The Risk Adjustment in Congenital Heart Surgery scores were more concordant with length of stay compared with Aristotle Basic Complexity scores (P < .0001).ConclusionsThe predictive value of Risk Adjustment in Congenital Heart Surgery is higher than that of Aristotle Basic Complexity. The use of Aristotle Basic Complexity or Risk Adjustment in Congenital Heart Surgery as risk stratification and trending tools to monitor outcomes over time and to guide risk-adjusted comparisons may be valuable

Late functional outcomes after repair of tetralogy of Fallot with atrioventricular septal defect: A double case-match control study

ObjectivesWe sought to elucidate late functional outcomes of the right ventricular outflow tract and atrioventricular valves after repair of tetralogy of Fallot with atrioventricular septal defect.MethodsFrom 1990 to 2010, the data from 41 patients who underwent repair were retrospectively reviewed. The median age at repair was 22.4 months (interquartile range, 10.8-41.6 months). Of the 41 patients, 13 (32%) had received previous palliations. The preoperative anatomic differences, physiologic differences, and long-term functional outcomes were determined using a double case-matched control with isolated tetralogy of Fallot and isolated atrioventricular septal defect.ResultsThe right ventricular outflow tract was reconstructed, with the pulmonary valve preserved in 23 patients (56%). There were 3 early deaths and no late deaths. Survival was 92.1% at 15 years. During a median follow-up period of 5.9 years (interquartile range, 0.14-13.7 years), 29 reinterventions were performed in 13 (32%) patients. Freedom from all reintervention at 15 years was 52.8%. Of the 29 procedures, 12 (41%) were related to the right ventricular outflow tract. Freedom from right ventricular outflow tract-related reintervention was greater in patients who had their pulmonary valve preserved (95% vs 70% at 10 years; P = .046). Reinterventions were performed for the atrioventricular valve in 2 (5%) patients and subaortic stenosis in 1 (2%) patient. Freedom from right ventricular outflow tract-related reintervention (tetralogy of Fallot with atrioventricular septal defect, 88.6% vs tetralogy of Fallot alone, 83.9% at 5 years; P = .809) and atrioventricular valve/left ventricular outflow tract-related reintervention (tetralogy of Fallot with atrioventricular septal defect, 95.2% vs atrioventricular septal defect alone, 86.0% at 5 years; P = .332) were comparable between the tetralogy of Fallot with atrioventricular septal defect and matched control groups.ConclusionsLate survival and atrioventricular valve function after repair of tetralogy of Fallot with atrioventricular septal defect were excellent. Pulmonary valve preservation and avoidance of an artificial conduit were associated with greater freedom from right ventricular outflow tract reintervention. In the current era, the surgically modified history of tetralogy of Fallot with atrioventricular septal defect is not significantly different from that of isolated tetralogy of Fallot or isolated atrioventricular septal defect

Biventricular repair in children with atrioventricular septal defects and a small right ventricle: Anatomic and surgical considerations

ObjectiveWe sought to characterize morphology and to evaluate a strategy of using biventricular repair in patients with a small right ventricle and an unbalanced atrioventricular septal defect.MethodsThirty-eight children with a small right ventricle and an atrioventricular septal defect underwent operative therapy. Thirty-two had biventricular repair, and 6 had single-ventricle palliation. A small right ventricle was defined on the basis of echocardiographic measurements expressed as the atrioventricular valve index (ie, right atrioventricular valve/left atrioventricular valve area) and as the ratio of right ventricular to left ventricular length. Validation of measurements in patients with a small right ventricle and an atrioventricular septal defect was achieved by comparison with balanced case-matched control subjects with atrioventricular septal defects.ResultsChildren with a small right ventricle and an atrioventricular septal defect had a lower atrioventricular valve index (mean, 0.41 ± 0.1 vs 0.52 ± 0.1 [control], P < .0001) and lower right ventricular/left ventricular length ratio (0.78 ± 0.1 vs 0.99 ± 0.17 [control], P < .0001). Children with a small right ventricle undergoing single-ventricle palliation had the smallest right ventricular dimensions. There were 4 operative deaths. Three patients with a small right ventricle and an atrioventricular septal defect who underwent biventricular repair and had an atrioventricular valve index of less than 0.50 required early reoperation for right ventricular inadequacy. A restrictive atrial fenestration was created in 11 infants. Survival at 10 years was 87% for patients undergoing biventricular repair versus 100% for control subjects (P = .042).ConclusionsExtending the use of biventricular repair in properly selected patients with a small right ventricle and an atrioventricular septal defect is feasible. An atrial fenestration improves the physiologic tolerance to repair in selected patients. The use of biventricular repair in children with atrioventricular valve indexes of less than 0.50 requires caution

Conventional and sutureless techniques for management of the pulmonary veins: Evolution of indications from postrepair pulmonary vein stenosis to primary pulmonary vein anomalies

ObjectiveWe have previously reported a limited but favorable experience with a novel sutureless technique for surgical management of postoperative pulmonary vein stenosis occurring after repair of total anomalous pulmonary venous drainage. Because this technique requires integrity of the retrocardiac space for hemostasis, extension of the technique to the primary repair of pulmonary vein anomalies requires evaluation. This analysis reviews our experience with the sutureless technique in patients with postrepair pulmonary vein stenosis, as well as our extension of the technique into primary repair of pulmonary vein anomalies.MethodsRetrospective univariable-multivariable analysis of all pulmonary vein stenosis procedures and sutureless pulmonary vein procedures over a 20-year period was performed. Cox proportional hazards modeling was used to identify variables associated with freedom from reoperation or death.ResultsSixty patients underwent 73 procedures, with pulmonary vein stenosis present in 65 procedures. The sutureless technique was used in 40 procedures. Freedom from reoperation or death at 5 years after the initial procedure was 49%. Unadjusted freedom from reoperation or death was greater with the sutureless technique for patients with postrepair pulmonary vein stenosis (P = .04). By using multivariable analysis, a higher pulmonary vein stenosis score was associated with greater risk of reoperation or death. After adjustment, the sutureless repair was associated with a nonsignificant trend toward greater freedom from reoperation or death (P = .12). Despite the absence of retrocardiac adhesions, operative mortality was not increased with the sutureless technique (P = .64). Techniques to control bleeding (intrapleural hilar reapproximation) and improve exposure (inferior vena cava division) were identified.ConclusionThe sutureless technique for postrepair pulmonary vein stenosis is associated with encouraging midterm results. Extension of the indications for the technique to primary repair appears safe with the development of simple intraoperative maneuvers

Pediatric heart transplantation: Improving results in high-risk patients

AbstractObjectives: Our institutional experience with 73 pediatric patients undergoing cardiac transplantation between January 1, 1990, and December 31, 1999, was reviewed to determine the impact of unconventional donor and recipient management protocols implemented to extend the availability of this therapy. Methods and results: The introduction of donor blood cardioplegic solution with added insulin was associated with a significant improvement in patient and graft survival (hazard ratio [Cox] = 0.25, P =.08), despite significantly longer ischemic times with this protocol compared with the use of crystalloid-based donor procurement techniques (P <.01). Eleven patients underwent intentional transplantation of ABO-incompatible donor hearts with the aid of a protocol of plasma exchange on bypass. In this subgroup, there were 2 early deaths caused by nonspecific graft failure (n = 1) and respiratory complications with mild vascular rejection (n = 1), and there was 1 late death caused by lymphoma. ABO-incompatible transplantation was not a risk factor for death by multivariate analysis. The postoperative course in these patients suggests minimal reactivity directed against incompatible grafts on the basis of low anti-donor blood group antibody production, in association with a favorable rejection profile. Ten of 13 patients requiring preoperative support with an extracorporeal membrane oxygenator survived transplantation; there were 3 additional late deaths in this subgroup (hazard ratio = 2.88, P =.05). Conclusions: The results with pediatric cardiac transplantation continue to improve as a result of changes in both surgical and medical protocols permitting successful treatment of patients conventionally considered at high risk or unsuitable for transplantation. (J Thorac Cardiovasc Surg 2001;121:782-91