Huiwen Chen

Investigation of somatic NKX2-5, GATA4 and HAND1 mutations in patients with tetralogy of Fallot.

Aims: Tetralogy of Fallot (TOF) is the most common type of congenital heart disease (CHD). Several genes essential for heart development have been identified. In recent years, there have been a few reports of the high frequency of somatic mutation in the heart tissues of CHD patients. The majority of findings were reported by the same investigators using formalin fixed tissues. In this study, we investigate the possibility of somatic mutation in fresh pathological cardiac tissues. Methods: We sequenced all exons and their boundaries of the NKX2-5, GATA4 and HAND1 genes from the right ventricular outflow tract muscle and peripheral blood of 38 unrelated non-syndromic TOF children who had undergone routine surgery. The same group of genes was also sequenced in the peripheral blood of 105 control subjects. We also compared the DNA yield in different tissue storage methods and sequenced 10 formalin fixed specimens. Results: Sequencing cardiac muscle and peripheral blood from the same patient showed identical findings. The previously reported p.Pro407Gln mutation in GATA4 gene and a novel heterozygous p.Ala58Glu mutation in HAND1 gene were identified in two of the 38 patients, both in the affected cardiac tissues and in the lymphocytes. These mutations were not seen in any control subjects. The formalin fixation rendered less DNA yield than the frozen method, but no artificial mutations were generated. Conclusions: Our study shows no evidence of somatic NKX2-5, GATA4 and HAND1 mutations playing a role in the pathogenesis of TOF. Our findings suggest that the GATA4 and HAND1 germline mutations are associated with non-syndromic CHD.

Total Anomalous Pulmonary Venous Connection: The Current Management Strategies in A Pediatric Cohort of 768 Patients

Background: Total anomalous pulmonary venous connection (TAPVC) is a rare form of congenital heart disease. This study describes current surgical treatment strategies and experiences in a cohort of patients from 2 congenital cardiac centers in Shanghai and Guangdong in China. Methods: This retrospective study included 768 patients operated on between 2005 and 2014. Although most patients (n=690) underwent conventional repair, a sutureless technique was used in 10% (n=78) of cases. A multilevel mixed-effects parametric survival model and a competing-risk analysis were used to analyze associated risk factors for death and recurrent pulmonary venous obstruction (PVO), respectively. Kaplan-Meier analysis was used to analyze the overall survival. The Nelson-Aalen cumulative risk curve was used to compare distributions of time with recurrent PVO. Results: The mean surgical age and weight were 214.9±39.2 days and 5.4±3.6 kg, respectively. Obstructed TAPVC (PVO) was documented in 192 (25%) of the 768 patients. There were 38 intraoperative deaths and 13 late deaths. A younger age at the time of repair (P=0.001), mixed (P=0.004) and infracardiac (P=0.035) TAPVC, preoperative PVO (P=0.027), prolonged cardiopulmonary bypass time (P<0.001), and longer duration of ventilation (P=0.028) were associated with mortality. The median follow-up was 23.2 months (range; 1–112 months). Among the 717 survivors, recurrent PVO was observed in 111 patients (15%). Associated risk factors for recurrent PVO included preoperative PVO (P<0.001), infracardiac TAPVC (P<0.001), mixed TAPVC (P=0.013), and prolonged cardiopulmonary bypass time (P<0.001). Sutureless technique was associated with a lower restenosis rate compared with conventional repair in patients with preoperative PVO (P=0.038), except in newborn patients (P=0.443). Reintervention for restenosis was performed in 24 patients. The function of most survivors (91%) was classified according to the New York Heart Association as functional class I or II. Conclusions: Surgical correction in patients with TAPVC with a biventricular anatomy can achieve an acceptable outcome. Risk factors such as a younger age at the time of repair, infracardiac and mixed TAPVC, and preoperative PVO were associated with a poorer prognosis.

Cone reconstruction of the tricuspid valve in Ebstein anomaly with or without one and a half ventricle repair

OBJECTIVE We sought to review our institutional experience and midterm results with cone reconstruction in Ebstein anomaly with or without one and a half ventricle repair to evaluate these 2 important surgical methods for the treatment of Ebstein anomaly. METHODS From January 1, 2004, to October 1, 2009, 30 consecutive patients with Ebstein anomaly underwent cone reconstruction. All patients underwent cone reconstruction, and 20 patients with severe Ebstein anomaly had a bidirectional cavopulmonary shunt constructed. The median age was 60 months (range, 2-192 months). Our criteria to define severe Ebstein anomaly include a severely enlarged right-sided chamber, significant abnormality of the septal leaflet of the tricuspid valve, and hemodynamic instability after cardiopulmonary bypass. Clinical or echocardiographic characteristics were studied both preoperatively and postoperatively. RESULTS There was 1 (3.3%) hospital death. Before the operation, tricuspid incompetence was moderate in 8 and severe in 22 patients. Postoperative early echocardiographic analysis showed that tricuspid incompetence was mild in 26 patients, moderate in 3 patients, and severe in 1 patient. After a median follow-up time of 22 months, tricuspid incompetence of 20 patients with bidirectional cavopulmonary shunt was mild in 15 and moderate in 4. Tricuspid incompetence of 10 patients without a bidirectional cavopulmonary shunt from the latest echocardiogram (median follow-up time, 32 months) was mild in 4, moderate in 4, and severe in 2 patients. For patients whose postoperative tricuspid incompetence was beyond mild among the 10 patients without a bidirectional cavopulmonary shunt, preoperative echocardiographic analysis shows a severely dilated right ventricle. CONCLUSIONS Addition of a bidirectional cavopulmonary shunt to cone reconstruction of the tricuspid valve should be considered for young patients with severe Ebstein anomaly who are at high risk of right ventricular failure after the operation.

Label-free quantitative proteomic analysis of right ventricular remodeling in infant Tetralogy of Fallot patients.

Tetralogy of Fallot (TOF) results in chronic progressive right ventricular (RV) pressure overload and shunt hypoxemia. We investigated the global changes in the proteome of RV among infant patients with and without TOF to gain an insight into early RV remodeling. One hundred and thirty-six differentially expressed proteins were identified using label-free LC-ESI-MS/MS analysis. Western blot results revealed that the expression of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 2 (PFKFB2) increased significantly in TOF patients; and levels of lysocardiolipin acyltransferase 1 (LCLAT1), lumican (LUM), and versican (VCAN) decreased significantly. QRT-PCR analysis showed that levels of PFKFB2 mRNA were markedly increased, but those of LCLAT1 and LUM were significantly decreased. VCAN mRNA showed no significant change in response to pathophysiology of TOF. The results of immunohistochemical staining were similar to those of Western blot analysis. Results of the proteomic analysis indicated that the level of glycolysis-related proteins had increased and levels of lipid-metabolism-related proteins had decreased. ECM proteins were found to be more down-regulated in TOF in the present study than in previous reports. Taken together, our findings may provide clues to both the metabolic inflexibility and ECM remodeling during the early RV remodeling, which occur in response to chronic hypoxia and long-term pressure overload in TOF patients.

Cardiomyocytes in Young Infants With Congenital Heart Disease: a Three-Month Window of Proliferation

Perinatal reduction in cardiomyocyte cell cycle activity is well established in animal models and humans. However, cardiomyocyte cell cycle activity in infants with congenital heart disease (CHD) is unknown, and may provide important information to improve treatment. Human right atrial specimens were obtained from infants during routine surgery to repair ventricular septal defects. The specimens were divided into three groups: group A (age 1–3 months); group B (age, 4–6 months); and group C (age 7–12 months). A dramatic fall in the number of Ki67 -positive CHD cardiac myocytes occurred after three months. When cultured in vitro, young CHD myocytes (≤3 months) showed more abundant Ki67-positive cardiomyocytes and greater incorporation of EdU, indicating enhanced proliferation. YAP1 and NICD—important transcript factors in cardiomyocyte development and proliferation—decreased with age and β-catenin increased with age. Compared with those of older infants, cardiomyocytes of young CHD infants (≤3 months) have a higher proliferating capacity in vivo and in vitro. From the perspective of cardiac muscle regeneration, CHD treatment at a younger age (≤3 months) may be more optimal.

Surgical repair for primary pulmonary vein stenosis: Single-institution, midterm follow-up

BACKGROUND Primary pulmonary vein stenosis (PVS) is a rare congenital heart condition and carries a poor prognosis. METHODS A retrospective review of 18 patients who underwent surgical therapy for primary PVS (2006-2014) was conducted. According to the degree of stenosis severity, the involved pulmonary veins (PVs) were divided into 3 categories: mild (34 veins), moderate (8), and severe (3). Pericardial patch venoplasty was used in 10 involved veins, endarterectomy in 11, and sutureless pericardial marsupialization in 19. RESULTS Median surgical age and weight were 19.8 (range: 7-100) months and 7.7 (range: 5.3-20.3) kg, respectively. Bilateral PVS was found in 10 patients (56%), and unilateral in 8 (44%). Moderate or severe stenosis was found more frequently in PVs on the left side (P = .035). Multivein involvement was more common in patients age ≤18 months than in older patients (75% vs 20%, P = .054). No early operative death occurred. Median length of hospital stay was 16 (range: 8-60) days. One subsequent death occurred (6%), at the 2-month follow up after discharge. Median follow-up time for the remaining patients was 29 (range: 2-91) months. Three of the 6 PVs treated for moderate stenosis, compared with 7 of the 34 treated for mild stenosis, developed restenosis, irrespective of the surgical strategy (P = .153). Most surviving patients remained in relatively good condition, in New York Heart Association functional class I or II. CONCLUSIONS Detailed morphologic evaluation of each PV involved is a consideration for surgery, and is closely related to the prognosis. Moderate or severe primary PVS is worse than mild PVS, and no differences were found in effectiveness among endarterectomy, pericardial patch venoplasty, and sutureless pericardial marsupialization in treating primary PVS.

Extracardiac Fontan with direct cavopulmonary connections: midterm results

OBJECTIVES The aim of this study was to analyse the midterm results following superior and inferior direct cavopulmonary connections (DCPC) to create a Fontan circulation in patients with functionally univentricular hearts. METHODS A retrospective review of patients operated on between January 2005 and December 2011 was carried out. RESULTS Thirty consecutive patients who underwent this type of operation were retrospectively reviewed. There were 18 (60%) males and 12 (40%) females, with a median age of 69 months (range 16-150 months) and median weight of 23 kg (range 11-46 kg). Aortic cross-clamping was used in 10 patients, with a median cross-clamp time of 40 min (range 23-99) and a median cardiopulmonary bypass (CPB) time of 135 min (range 76-179 min). The remaining 20 patients were operated on without aortic cross-clamping. Their median CPB time was 104 min (range 78-139 min). Fenestration was performed in 16 patients. The associated intracardiac procedures were performed in 10 patients. The follow-up period ranged from 2 months to 6 years. Operative mortality and late mortality after discharge was zero. The major postoperative complications included supraventricular tachycardia in one patient, oliguria and peritoneal dialysis in one and chest drainage (>30 ml/day) persisting >7 days in five (20%). One patient developed sinus bradycardia in association with sinus pauses 2 months after discharge. One patient developed pericardial effusion 1 month after discharge. A computational fluid dynamic study was performed in one patient. The computational fluid dynamic study showed that DCPC may have a better power efficiency. CONCLUSIONS Superior and inferior DCPCs to create a Fontan circulation in appropriately selected patients with functionally univentricular hearts can be performed with a low risk and a low rate of reinterventions. The midterm results are favourable.

Late complete atrioventricular block and tricuspid regurgitation after percutaneous closure of a perimembranous ventricular septal defect

Percutaneous closure of a perimembranous ventricular septal defect (VSD) is nowadays a valuable alternative to surgical closure. Preliminary results regarding the safety of this device and the low incidence of aortic and tricuspid regurgitation are encouraging. However, owing to the close proximity of the perimembranous VSD to the conduction system, concern about atrioventricular block has been raised. The published reports on this complication describe the latest onset of complete atrioventricular block (CAVB), presenting at 37.8 months after implantation. We report here 1 case of delayed CAVB with severe tricuspid regurgitation occurring 5 years after implantation of an eccentric Amplatzer perimembranous VSD occluder (APmVSDO; AGA Medical, Golden Valley, Minn).

Results of one-and-a-half-patch technique for repair of complete atrioventricular septal defect with a large ventricular component

OBJECTIVES Management of complete atrioventricular (AV) septal defect (CAVSD) with a large ventricular component (>1 cm) remains controversial. The purpose of this study was to assess the feasibility of the one-and-a-half patch technique in repairing this lesion. METHODS This was a retrospective review of patients undergoing surgical repair of CAVSD with a large ventricular component (>1 cm). Of the 51 patients who were identified in our database (2005-13), 18 underwent the two-patch repair, 12 underwent the modified single-patch repair and 21 underwent the one-and-a-half-patch repair. The CAVSD was combined with tetralogy of Fallot (TOF) in 3 patients and with double-outlet right ventricle (DORV) and pulmonary stenosis (PS) in two individuals in the one-and-a-half-patch group. RESULTS There were two hospital deaths in the two-patch group, but no deaths in the other two groups. The modified single-patch procedure was associated with the shortest myocardial ischaemic and cardiopulmonary bypass (CPB) times, the two-patch procedure was associated with the longest times and the 1.5-patch procedure times were intermediate. Median follow-up was 35 months (41.6 ± 27.2 months). There were no reoperations in the 1.5-patch group while reintervention was required for 1 patient in the two-patch group (P = 0.252) and 3 patients in the modified single-patch group (P = 0.017). The function of the reconstituted AV valves improved after operation in the 1.5-patch group. No patient in these three groups developed subsequent left ventricular outflow tract obstruction. CONCLUSIONS The 1.5-patch technique is an attractive clinical option. It produces acceptable mid-term results comparable with two conventional techniques in patients with similarly sized ventricular component.

Primary complete repair of interrupted aortic arch with associated lesions in infants.

Interrupted aortic arch (IAA) is a complicated congenital heart disease requiring an individualized management strategy. We reported the results for surgical repair of IAA with associated anomalies.