Jinfen Liu

Meta Analysis of the Association between MTHFR C677T Polymorphism and the Risk of Congenital Heart Defects

Methylenetetrahydrofolate reductase (MTHFR) polymorphism C667T has been associated with congenital malformation; this common missense mutation in the MTHFR gene may reduce enzymatic action, and may be involved in the etiology of congenital heart defects (CHD). The aim of this study was to investigate the relationship of the MTHFR C677T polymorphism with the risk of CHD in children with CHD and their parents by meta‐analysis. Studies were identified by searching electronic literature for papers before 2011, focusing on MTHFR C667T and the risk of CHD. All data were analyzed using the fixed effects model in Cochrane Review Manager 5.1.1. Twenty eligible case‐control and family‐based studies were included. Overall analysis yielded pooled odds ratios (OR) of 1.55 (95%CI 1.25–1.93), 1.84 (95%CI 1.23–2.74) and 1.20 (95%CI 0.94–1.54) for fetal, paternal and maternal MTHFR TT genotypes in case‐control studies, respectively, but yielded a summarized OR of 0.9 (95%CI 0.97–1.12) in family‐based studies. Our results suggested that the fetal and paternal MTHFR C667T gene may be associated with an increased occurrence of CHD. Further larger studies should be performed to investigate the interaction between maternal genetic polymorphism, folic acid intake and hyperhomocysteinemia, and the development of 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.

Nitric Oxide in Conjunction With Milrinone Better Stabilized Pulmonary Hemodynamics After Fontan Procedure

Inhaled nitric oxide (iNO) has been used for patients with increased pulmonary vascular resistance (PVR) shortly after Fontan operation, but repeat deterioration of PVR during or shortly after its withdrawal remains a major concern. Milrinone, a phosphodiesterase type 3 (PDE3) inhibitor, can also reduce PVR for postoperative patients with pulmonary hypertension. We hypothesized that iNO, in conjunction with milrinone, can provide additive benefits for pulmonary hemodynamics and reduce the occurrence of iNO withdrawal failure/rebound. Thirty-one patients with marked elevation of transpulmonary pressure gradient (TPG, >10 mm Hg) or central venous pressure (CVP, >15 mm Hg) after modified fenestrated Fontan operation were prospectively randomized into two groups, that is, group iNO (iNO at approximately 10 ppm, n = 15) and group iNO + Mil (iNO at approximately 10 ppm and milrinone at 0.5 microg/kg/min, n = 16). Hemodynamics, arterial blood oxygenation, and occurrence of withdrawal failure/rebound were compared between the two groups. Combined application of iNO and milrinone resulted in (i) more significant decrement of CVP (19.6 +/- 3.5% in group iNO + Mil vs. 15.2 +/- 4.6% in group iNO, P < 0.05) and TPG (18.2 +/- 4.8% in group iNO + Mil vs. 15.3 +/- 2.6% in group iNO, P < 0.05), (ii) more significant increment of systolic systemic arterial pressure (8.7 +/- 2.7% in group iNO + Mil vs. 5.2 +/- 3.1% in group iNO, P < 0.05), and (iii) more significant improvement of arterial oxygen saturation (9.3 +/- 3.2% in group iNO + Mil vs. 6.8 +/- 2.8% in group iNO, P < 0.01). Occurrence of iNO withdrawal failure during its weaning or rebound after its discontinuation was significantly lower in group iNO + Mil. The combined use of iNO and milrinone provided additive benefits as compared with exclusive use of iNO for patients with elevated PVR after Fontan procedure.

β2-Adrenergic receptor-induced transactivation of epidermal growth factor receptor and platelet-derived growth factor receptor via Src kinase promotes rat cardiomyocyte survival.

Chronic stimulation of the β‐AR (adrenergic receptor) promotes apoptosis of cardiomyocytes, which is implicated in cardiac dysfunction. β1‐AR and β2‐AR are the main subtypes of β‐AR that exert distinct effects on the survival of cardiomyocytes. To clarify the physiological roles of β1‐AR and β2‐AR in cardiomyocytes, the effects of β1‐AR or β2‐AR knockdown on the survival of H9c2 cardiomyocytes was investigated. Knockdown of β2‐AR, but not β1‐AR, suppressed the phosphorylation of EGFR (epidermal growth factor receptor) and PDGFR (platelet‐derived growth factor receptor) induced by ISO (isoprenaline). The EGFR inhibitor, AG1478, attenuated ERK (extracellular‐signal‐regulated kinase) activation and partially decreased cell survival. Pretreatment with AG1296, a PDGFR inhibitor, abolished ISO‐induced Akt (also known as protein kinase B) phosphorylation and led to a decrease in cell viability. In addition, the Src tyrosine kinase inhibitor, PP2, blocked ISO‐mediated both Akt and ERK activation and heavily suppressed viability. Accordingly, in primary neonatal rat cardiomyocytes, the β2‐AR inhibitor, but not the β1‐AR inhibitor, abrogated the transactivation of EGFR and PDGFR, which was respectively related to Akt and ERK activation. The results show that β2‐AR transactivates PDGFR and EGFR, thereby promoting survival of cardiomyocytes.

Use of Computational Fluid Dynamics to Estimate Hemodynamic Effects of Respiration on Hypoplastic Left Heart Syndrome Surgery: Total Cavopulmonary Connection Treatments

Total cavopulmonary connection (TCPC), a typical kind of Fontan procedure, is commonly used in the treatment of a functional single ventricle. The palliative cardiothoracic procedure is performed by connecting the superior vena cava and the inferior vena cava to the pulmonary arteries. Due to the difficulty of direct study in vivo, in this paper, computational fluid dynamics (CFD) was introduced to estimate the outcomes of patient-specific TCPC configuration. We mainly focused on the influence of blood pulsation and respiration. Fast Fourier transforms method was employed to separate the measured flow conditions into the rate of breath and heart beat. Blood flow performance around the TCPC connection was investigated by analyzing the results of time-varying energy losses, blood flow distribution rate, local pressure, and wall shear stress distributions. It was found that the value of energy loss including the influence of respiration was 1.5 times higher than the value of energy loss disregarding respiratory influences. The results indicated that the hemodynamic outcomes of TCPC treatment are obviously influenced by respiration. The influence of respiration plays an important role in estimating the results of TCPC treatment and thus should be included as one of the important conditions of computational haemodynamic analysis.

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.

Influence of antegrade pulmonary blood flow on the hemodynamic performance of bidirectional cavopulmonary anastomosis: A numerical study

The role and effect of preserved antegrade pulmonary blood flow (APBF) at the time of bidirectional cavopulmonary anastomosis (BCPA) in the management of single-ventricle physiology is controversial. We investigated the influence of APBF on the fluid dynamics of BCPA connection using computational fluid dynamics (CFD). Patient-specific, three-dimensional geometry of a BCPA connection with native pulmonary artery (PA) trunk was reconstructed and transient CFD simulations were done at four predetermined mean flow rates of PA trunk (0.5L/min, 1L/min, 1.5L/min and 2L/min). During a cardiac cycle, the flow ratio of left pulmonary artery (LPA)/right pulmonary artery (RPA) increased from 1.91 to 2.50, and average control volume power loss increased from 0.76 mW to 18.05 mW when the mean flow rate of PA trunk changed from 0.5L/min to 2L/min. The pulsatility of pressures in LPA, RPA and superior vena cava became more prominent as the amount of APBF increased. Local fluid structures in the connection area at four levels of APBF differed from each other.

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 management of congenital tracheal stenosis associated with tracheal bronchus and congenital heart disease

OBJECTIVES Congenital tracheal stenosis (CTS) is variable in patients with tracheal bronchus and congenital heart disease (CHD). Tracheoplasty remains a high-risk surgical treatment. METHODS From January 2007 to December 2014, 24 CTS patients (10 males and 14 females; age 20.6 ± 13.6 months) with tracheal bronchus and CHD underwent one-stage surgical correction. Clinical features of all patients included dyspnoea, or recurrent pulmonary infections. There was long-segment CTS in 13 cases (54%), and 4 cases were associated with a bridging bronchus. Less than 50% of normal tracheal size was identified in 21 cases. Complete tracheal or bronchial rings were identified in all cases. Operative techniques included: tracheal end-to-end anastomosis in 11 cases and slide tracheoplasty in 13 cases, which included 11 cases of right upper lobe bronchus (RULB) opposite side-slide tracheoplasty. RESULTS There were 2 operative deaths, due to postoperative tracheomalacia or residual main bronchial stenosis. The duration of postoperative hospital stay was 7-59 days, with an average of 19 days. Follow-up was completed in 19 cases. The follow-up duration was from 1 month to 7 years. Tracheal granulation occurred in 1 case. Clinical symptoms were significantly improved in the remaining patients. CONCLUSIONS Tracheal bronchi have special anatomical features. The techniques of tracheal end-to-end anastomosis or side-slide tracheoplasty can be used to correct tracheal stenosis with satisfactory outcomes.