Severe hypoxemia after radiofrequency ablation for atrial fibrillation in palliatively repaired tetralogy of Fallot: A case report

BACKGROUND Patients with tetralogy of Fallot(TOF)often have arrhythmias,commonly being atrial fibrillation(AF).Radiofrequency ablation is an effective treatment for AF and does not usually cause severe postoperative hypoxemia,but the risk of complications may increase in patients with conditions such as TOF.CASE SUMMARY We report a young male patient with a history of TOF repair who developed severe hypoxemia after radiofrequency ablation for AF and was ultimately confirmed to have a new right-to-left shunt.The patient subsequently underwent atrial septal occlusion and eventually recovered.CONCLUSION Radiofrequency ablation may cause iatrogenic atrial septal injury;thus possible complications should be predicted in order to ensure successful treatment and patient safety.

Pulmonary Hypertension Crisis in Patient with Tetralogy of Fallot and Mixed Total Anomalous Pulmonary Vein Connection after the Primary Correction:A Rare Case Report

Tetralogy of Fallot(TOF)with total anomalous pulmonary vein connections(TAPVC)is a rare type of complex congenital heart disease among all TOF cases.Co-presentation of major aortopulmonary collateral arteries(MAPCAs)compensates for the lack of central pulmonary bloodflow and decreases the severity of right-to-left shunting in TOF.We present a case of a 2-year-old child with complex diagnoses of TOF,TAPVC,a large secun-dum atrial septal defect(ASD),and intraoperatively identified MAPCAs.She underwent surgery to repair the TAPVC,valve-sparing reconstruction of the right ventricular outflow tract,interventricular defect closure,and the creation of patent foramen ovale(PFO).After the operation,hemodynamic instability happened along with sudden blood pressure drop,desaturation,and increased central venous pressure,which subsided after adminis-tering inhalational nitric oxide(NO).A postoperative pulmonary hypertension crisis was suggested when the patient experienced recurrent symptoms after the termination of NO.Echocardiographicfindings of a D-shaped left ventricle(LV),right-to-left PFO shunt and high tricuspid valve gradientfirmly established the diagnosis.It was subsequently managed with continuous NO inhalation and sildenafil,which rendered a satisfactory outcome.Repaired TOF and TAPVC could be at particular risk of developing pulmonary hypertension crisis,especially in the presence of MAPCAs due to possible remodeling of the pulmonary vasculature.Furthermore,a relatively non-compliant LV function and small left atrial size may exacerbate the risk of developing postcapillary pulmonary hypertension after TAPVC repair.A successful postoperative outcome calls for a meticulous preoperative analysis of the anatomical lesions,as well as careful monitoring.

Single-Cell RNA Sequencing Reveals Potential for Endothelial-to-Mesenchymal Transition in Tetralogy of Fallot

Background:Tetralogy of Fallot(TOF)is a very common cyanotic congenital heart disease.Endothelial-to-mesenchymal transition(EndoMT)is recognized as a physiological mechanism involved in embryonic heart development and endothelial formation.However,there is still a gap in the reports related to the mechanism of EndoMT development in TOF.Methods:First,transcriptomic data of single cell nuclei of TOF and Donor were obtained based on the Gene Expression Omnibus(GEO)database,and the data were normalized and clus-tered by dimensionality reduction using the Seurat package.Subsequently,differentially expressed genes(DEGs)between TOF and Donor were screened using the“FindMarkers”function,and the gene sets of interest were enriched.Finally,to characterize the dynamics of EndoMT occurrence in TOF,we performed pseudotime cell tra-jectory inference as well as utilized SCENIC analysis to probe the gene regulatory networks(GRNs)dominated by transcription factors(TFs)in endothelial cells.Results:We identified a total of six cell clusters based on single-cell nuclear transcriptome data from TOF and Donor.We found that 611 genes with up-regulated expression within TOF showed conversion to mesenchyme.By subdividing endothelial cell subtypes,endothelial cells 2 were shown to be involved in cell adhesion,migration and extracellular matrix processes.Pseudo-time and SCENIC analyses showed that endothelial cell 2 has EndoMT potential.In addition,ERG and TEAD1 are TFs that play key reg-ulatory roles in this subtype,and both of their target genes are also highly expressed in TOF.This demonstrates that ERG and TEAD1 effectively promote the EndoMT process.Conclusion:Our study reveals the molecular mechanisms underlying the development of EndoMT in TOF,which demonstrates that manipulating the endothelial-to-mesenchymal transition may offer unprecedented therapeutic potential for the treatment of TOF.

Pulmonary and tricuspid regurgitation after Tetralogy of Fallot repair: A case report

BACKGROUND Tetralogy of Fallot(TOF)is one of the most common congenital heart defects,and surgery is the primary treatment.There are no precise guidelines on the treatment protocol for tricuspid regurgitation(TR)as a common complication of TOF repair.The timing for treatment in patients presenting with valve regurgitation after TOF repair is often difficult to determine.Here,we report the first case of sequential treatment of pulmonary and TR using interventional therapy.CASE SUMMARY We present the case of a 52-year-old female patient,who had a history of TOF repair at a young age.A few years later,the patient presented with pulmonary and tricuspid regurgitation.The symptoms persisted and TR worsened following percutaneous pulmonary valve implantation.Preoperative testing revealed that the patient’s disease had advanced to an intermediate to advanced stage and that her general health was precarious.Because open-heart surgery was not an option for the patient,transcatheter tricuspid valve replacement was suggested.This procedure was successful,and the patient recovered fully without any adverse effects.This case report may serve as a useful resource for planning future treatments.CONCLUSION Treatment of both valves should be considered in patients with tricuspid and pulmonary regurgitations following TOF repair.The interventional strategy could be an alternative for patients with poor general health.

Evaluation of Right Ventricular Global Longitudinal Function in Patients with Tetralogy of Fallot by Two-dimensional Ultrasound Speckle Tracking Imaging

Quantification of right ventricular(RV)volume and function remains a challenge because of RV complex geometry by conventional echocardiography.The purpose of this study was to assess RV global longitudinal function in patients with tetralogy of Fallot(TOF)by 2-dimensional ultrasound speckle tracking imaging(STI).Thirty-eight patients with TOF were enrolled in this study and divided into child group(n=25)and adult group(n=13)according to age.Thirty-eight age-and sex-matched normal subjects were selected as c...

Appropriate Heart Rate in a Patient with Repaired Tetralogy of Fallot

Appropriate heart rate in a failing pulmonary ventricle remains unknown, particularly in congenital heart diseasewith unique hemodynamics. A 71-year-old male with repaired tetralogy of Fallot and a pacemaker for a sinusnode dysfunction suffered from heart failure symptoms with preserved left ventricular function. Simply changingthe pacemaker’s lower rate from 60 to 75 bpm, New York Heart Association classification improved from III to II,and hemodynamic parameters drastically improved. We regarded this case as informative. Appropriate heart ratecould be higher in congenital patients with failing right and non-failing left ventricles than in adults with malfunctioningLV.

Growth of the Pulmonary Valve Annulus after the Modified Blalock-Taussig Shunt in Patients with Tetralogy of Fallot

Background:The surgical outcomes of tetralogy of Fallot(TOF)have evolved dramatically and have resulted in lower mortality rate.Currently,the many cardiac centers have a trend to early single-stage complete repair more than a staged repair.However,the patients who have an early primary repair were required transannular patch augmentation of a pulmonary valve frequently.This effect has been developed a chronic pulmonary insufficiency may lead to right ventricular dilation,dysfunction.In this era,the aim of treatment of TOF is attempted to preserve pulmonary valve annulus for prevent right ventricular dysfunction in the future.The systemic to pulmonary artery shunt is a palliative procedure or known as staged repair for symptomatic patients with TOF.The modified Blalock-Taussig shunt(mBTS)is the most useful systemic to pulmonary shunt and perform as an initial procedure before complete repair.The mBTS can provide increase pulmonary blood flow as well as improve oxygenation and also promote pulmonary artery(PA)growth.However,the effect of this procedure to promote growth of a pulmonary valve annulus is still debate.Objectives:To compare a growth of pulmonary valve annulus between after staged repair and primary repair in patients with TOF(without pulmonary atresia).Methods:A retrospective case-control study,review of patients with TOF underwent total repair at our hospitals from January 2005 and December 2017 was performed,a total number of 112 patients underwent TOF repair.Twenty-nine patients(26%)underwent a staged repair(mBTS group)and 83(74%)underwent total repair only or primary repair(PR group).We evaluated diameter of pulmonary valve annulus by using echocardiography at the time of first diagnosis and before complete repair on both groups.Results:The age of diagnosis of mBTS group were younger than PR group(p=0.011).Therefore,pulmonary valve annuls were smaller in mBTS group.(Z-score,−2.93±1.42 vs.−1.89±0.97;p=0.001).However,the growth potential of pulmonary valve annulus was increase more than PR group significantly(Z-score,−1.46±1.02 vs.−2.11±1.19;p=0.009)Even though a patent ductus arteriosus was found commonly in PR group(p=0.018).Conclusions:Our results suggest the systemic to pulmonary shunt or mBTS can promote growth of pulmonary valve annulus in patients with TOF.

Pulmonary Perfusion Asymmetry in Patients after Repair of Tetralogy of Fallot: A 4D Flow MRI-Based Study

Background:Repaired Tetralogy of Fallot(rTOF)patients may have residual lesions such as main(MPA)and branch pulmonary artery stenosis(BPAS).While MPA stenosis is well studied,few data are available on BPAS in rTOF.We aimed to describe pulmonary perfusion in a large paediatric cohort of rTOF and its impact on right ventricular and outflow-tract hemodynamics using 4D flow CMR.Methods:130 consecutive patients(mean age at CMR 14.3±4.6 years)were retrospectively reviewed.96 patients had transannular patch without valve preservation while 34 patients had conserved annulus or valved conduit.A pulmonary blood flow ratio(right pulmonary artery(RPA)/left pulmonary artery(LPA))between 0.75 and 1.56 was considered normal.Results:Asymmetric pulmonary perfusion was present in 59/130 patients(45%),with 54/59(91%)having left lung hypoperfusion(blood flow ratio>1.56).RPA/LPA perfusion ratio in the whole cohort was independently associated with the LPA Z-score(−0.053,p=0.007),the RPA regurgitant fraction(RF)(0.013,p=0.011)and previous LPA stenting(0.648,p=0.004).Decreasing LPA%perfusion(and conversely increasing RPA%perfusion)was significantly associated with higher MPA diameter Z-score(−0.06,p=0.007).On multivariate analysis,MPA Z-score was independently associated with pulmonary RF(0.48,p<0.001)and with right ventricular indexed volumes(coefficient 3.6,p=0.023).In patients with transannular patch repair,asymmetric pulmonary flow was an independent predictor of right ventricular ejection fraction(RVEF)(−3.66,p=0.04).Conclusions:Pulmonary perfusion asymmetry is frequent in rTOF and is associated with abnormal right ventricular and outflow-tract hemodynamics,including MPA dilatation and decreased RVEF in patients after transannular patch.

Relation or Influence of RVOTO in the Inflammatory Response to Reoxygenation in Patients with Tetralogy of Fallot

Background:This study evaluated differential inflammatory response to cardiopulmonary bypass reoxygenation in tetralogy of Fallot repair.Methods:We performed a retrospective study at a cardiovascular center from 2012 to 2018,including 500 patients aged 1 week–18 years who received complete repair of tetralogy of Fallot.Patients were grouped according to tertiles of preoperative RVOT gradient on echocardiography into mild,moderate,and severe stenosis.We measured the highest perfusate oxygenation(PpO_(2))during aortic occlusion as independent variable.Primary outcome was systemic inflammatory response syndrome(SIRS)within 7 days postoperatively or the time of death or discharge.Results:Overall,rate of SIRS was 24.2% without significant differences among three groups(P>0.05).Older age,male,and smaller indexed left ventricular end-diastolic volume is independent risk factor of SIRS.There were significant interactions between RVOT stenosis and PpO2 on SIRS(P interaction=0.011):higher PpO_(2) was associated with a greater SIRS risk among combined moderate and severe stenotic children(OR 1.46395%CI[1.080,1.981]per-SD increase,P=0.014)but not among mild stenotic children(OR 0.900[0.608,1.333]per-SD increase;P=0.600),independent of covariates.Conclusion:The association of PpO_(2) with SIRS was modified by RVOT obstruction severity in tetralogy of Fallot repair.

Contemporary Patterns of Management of Tetralogy of Fallot:Data from a Single Center in China

Background:There is scarce research on large cohorts with tetralogy of Fallot(TOF)from China.The database in Fuwai Hospital was reviewed to ascertain current trends in the management of TOF and to determine the prevalence of various surgical techniques and the optimal early outcome.Methods:This cross-sectional study included 1861 patients who underwent surgery between 2012 and 2017 and were aged 0-18 years old with a primary diagnosis of TOF.A total of 1760 eligible patients were included in the analyses.Results:A total of 1683 patients underwent repair of TOF as a one-stage operation(primary repair).Sixty-one patients underwent repair of TOF after prior palliation.Of patients who underwent one-stage repair(n=1683):858 were 6 months to 1 year old,421 were 1 to 2 years old,251 were 2-18 years old,and 145 were 3 to 6 months old.Of patients who underwent repair following prior palliation(n=61),58(95.1%)were older than 1 year of age.Of 1744 complete repairs,986(56.0%)had annulus-sparing(AS)repair.Total in-hospital mortality was 15 of 1744(0.9%)for complete repair(including one-stage and staged repairs).The total incidence of the optimal early outcome was 78.2%in terms of a composite of the absence of death in the first year,significant right ventricular outflow tract obstruction,significant pulmonary valve insufficiency,or catheter or surgical reintervention.Conclusions:Surgical correction in patients with TOF can achieve an acceptable outcome in terms of death and reintervention.Primary repair at 6 months to 1 year of age is the most prevalent strategy in our centre.However,the relatively high incidence of early undesirable surgical adequacy of the pulmonary valve(PV)represents a wake-up call.

Surgical Treatment of Tetralogy of Fallot with Pulmonary Valve Agenesis in a 22 Years Old Patient

Agenesis of pulmonary valve is a rare variant and severe form of Tetralogy of Fallot (ToF). The evolution is usually marked by respiratory and cardiac failure at early age, which needs early surgical correction. Uncorrected treatment of Tetralogy of Fallot diagnosed at adult age is infrequent and only few studies have been described. We present here a rare case of a 22 years old patient who presented with dyspnea since childhood. Subsequent investigations allowed diagnosis of treatment of Tetralogy of Fallot with agenesis of the pulmonary valve. Following the assessment, the patient underwent a surgical repair and the recovery was uneventful. The management of treatment of Tetralogy of Fallot with pulmonary valve agenesis in adult period remains complex, requiring different surgical techniques.

A Case Report of Pediatric Cerebral Venous Thrombosis with Undiagnosed Complex Congenital Heart Disease: Tetralogy of Fallot with OS ASD: A Cataclysmic Ending

Cerebral Venous Sinus Thrombosis (CVST/CSVT) is occlusion of cerebral veins and venous sinuses of brain secondary to blood clot formation resulting in hindrance in the blood drainage system in brain, leading to disturbances the internal homeostasis of brain, raised intracranial pressure, cerebral edema, and 50% of cases will have venous infarction or venous hemorrhage (stroke). CVST although being a Rare disorder but may be more common in children than adults with greater risk in neonatal period i.e. first 28 days of life. Here we are discussing a case of Pediatric CVST in a 7-month-old baby boy who presented to Emergency Room (ER) with recurrent discrete episodes of vomiting, fever, seizures, drowsiness and respiratory distress. The fatal outcome in our child was attributed to delayed presentation in a tertiary care center, hence missed early diagnosis and treatment. In this child the CVST could be result of amalgamation of complex underlying ongoing multiple pathological processes: an acute systemic illness like sepsis, severe dehydration, undiagnosed and untreated complex congenital heart disease, tetralogy of fallot with osteum secondum atrial septal defect, worsening the coagulopathy. It takes this case even more unique. This discussion is to bring focus on the importance of knowledge about CVST amongst emergency physicians and primary care physicians, specially managing this rare disorder with flummox presentation mimicking other more common disorders, especially in pediatric and neonatal population where definitive history and chief complaints are often vague and difficult to obtain, making it more difficult to diagnose. We the authors hence reporting this case with intent to spread awareness of CVST, how to doubt it, detect it and then manage it, especially in places like Chhattisgarh, India, where CVST is not so uncommon. We believe early diagnosis, early presentation to tertiary care center with aggressive early treatment can significantly reduce the mortality. Should the parents brought the baby early to any tertiary care center owing to his complex deteriorating symptoms like high grade fever progressed to drowsiness and seizure episodes, could there be a different outcome for this child as well as his parents.

Quadrivalvar Rheumatic Cardiopathy in Tetralogy of Fallot in an Adult—A Case Report

Rheumatic involvement of all four heart valves is uncommon and its association with congenital heart disease is very rare. Tetralogy of Fallot is a frequent cyanotic congenital heart disease with a survival beyond middle age. Background of this case report described the rheumatic involvement of all four heart valves (quadrivalvar rheumatic cardiopathy) with stenotic lesions of semilunar valves (aortic and pulmonary valves) and regurgitant lesions of atrioventricular valves (mitral and tricuspid valves) in Tetralogy of Fallot in a 48-year old asymptomatic female, detected by transthoracic two dimensional echocardiography in Thoothukudi region of India.

Preoperative serum cortisone levels are associated with cognition in preschool‑aged children with tetralogy of Fallot after corrective surgery:new evidence from human populations and mice

Background Tetralogy of Fallot(TOF)is the most common cyanotic congenital heart disease.Children with TOF would be confronted with neurological impairment across their lifetime.Our study aimed to identify the risk factors for cerebral morphology changes and cognition in postoperative preschool-aged children with TOF.Methods We used mass spectrometry(MS)technology to assess the levels of serum metabolites,Wechsler preschool and primary scale of intelligence-Fourth edition(WPPSI-Ⅳ)index scores to evaluate neurodevelopmental levels and multimodal magnetic resonance imaging(MRI)to detect cortical morphological changes.Results Multiple linear regression showed that preoperative levels of serum cortisone were positively correlated with the gyrification index of the left inferior parietal gyrus in children with TOF and negatively related to their lower visual spaces index and nonverbal index.Meanwhile,preoperative SpO_(2) was negatively correlated with levels of serum cortisone after adjusting for all covariates.Furthermore,after intervening levels of cortisone in chronic hypoxic model mice,total brain volumes were reduced at both postnatal(P)11.5 and P30 days.Conclusions Our results suggest that preoperative serum cortisone levels could be used as a biomarker of neurodevelopmental impairment in children with TOF.Our study findings emphasized that preoperative levels of cortisone could influence cerebral development and cognition abilities in children with TOF.

Mitogen-activated protein kinase signal pathways play an important role in right ventricular hypertrophy of tetralogy of Fallot

Background Tetralogy of Fallot （TOF） is the most common malformation of children with an incidence of approximately 10% of congenital heart disease patients. There can be a wide spectrum to the severity of the anatomic defects, which include ventricular septal defect, aortic override, right ventricular outflow tract obstruction, and right ventricular hypertrophy. We examined the relationship between right ventricular hypertrophy in patients with TOF and the gene expression of factors in the mitogen-activated protein kinase （MAPK） signal pathway. Methods To gain insight into the characteristic gene（s） involved in molecular mechanisms of right ventricular hypertrophy in TOF, differential mRNA and micro RNA expression profiles were assessed using expression-based micro array technology on right ventricular biopsies from young TOF patients who underwent primary correction and on normal heart tissue. We then analyzed the gene expression of the MAPK signal pathway using reverse transcription-polymerase chain reaction （RT-PCR） in normals and TOF patients. Results Using the micro RNA chip V3.0 and human whole genome oligonucleotide microarray VI.0 to detect the gene expression, we found 1068 genes showing altered expression of at least two-fold in TOF patients compared to the normal hearts, and 47 micro RNAs that showed a significant difference of at least two-fold in TOF patients. We then analyzed these mRNAs and micro RNAs by target gene predicting software Microcosm Targets version 5.0, and determined those mRNA highly relevant to the right ventricular hypertrophy by RT-PCR method. There were obvious differences in the gene expression of factors in the MAPK signal pathway when using RT-PCR, which was consistent to the results of the cDNA microarray.Conclusion The upregulation of genes in the MAPK signal pathway may be the key events that contribute to right ventricular hypertrophy and stunted angiogenesis in patients with TOF.

Long-term outcome of correction of tetralogy of Fallot in 56 adult patients

Background Although most patients with tetralogy of Fallot undergo radical repair during infancy and childhood,patients that remain undiagnosed and untreated until adulthood can still be treated.This study aimed to evaluate longterm outcomes of adult patients with tetralogy of Fallot who were treated surgically,and to determine the predictors of postoperative pulmonary regurgitation.Methods Fifty-six adult patients underwent complete surgical repair.Forty-three patients （76.8%） required a transannular patch.Systolic,diastolic,and mean pressure in the main pulmonary artery were measured after repair.Results The early mortality rate was 3.6%.The 16-year survival rate was （84.4±11.5）%.Late echocardiography revealed 41 patients with transannular patch who had pulmonary regurgitation,consisting of mild pulmonary regurgitation in 28 patients,moderate in eight,and severe regurgitation in five patients.In addition,there was right ventricular outflow tract stenosis in nine patients,moderate/severe tricuspid valve regurgitation in seven,and residual ventricular septal defect in five.Logistic regression analysis demonstrated that the mean pulmonary pressure measured just after repair predicted late pulmonary regurgitation.Conclusions The long-term survival of surgically treated adult patients with tetralogy of Fallot is acceptable.The mean pressure 〉20 mmHg in the main pulmonary artery measured right after surgical repair may be a feasible reference to time the reconstruction of the pulmonary valve.

Expression of Cx43-related microRNAs in patients with tetralogy of Fallot

Background:Abnormal expression of connexin 43(Cx43)has been reported to play an important role in the development of conotrunccal anomalies.However,less is known about the underlying reason for its abnormal expression.MicroRNAs(miRNAs),as an important part of gene expression regulation,have been implicated in some cardiac diseases.This study aimed to investigate the expression of Cx43 and its related miRNAs in patients with tetralogy of Fallot(TOF),and illustrate the potential role of abnormal miRNAs regulation to Cx43 expression in the pathology of TOF.Methods:Real-time polymerase chain reaction was used to detect the expression of Cx43 and 10 Cx43-related miRNAs in the myocardium from 30 TOF patients and 10 normal controls.Immunohistochemistry was used to detect Cx43 protein expression.Putative miRNA binding sites in the 3'UTR of Cx43 were examined in 200 TOF patients and 200 healthy individuals,using Sanger sequencing,to exclude sequence variations resulting in binding diffi culties of miRNAs.Results:Cx43 mRNA and protein expression in the myocardium tissue was significantly increased in TOF patients.The expression of MiR-1 and 206 was significantly decreased in the TOF patients as compared with the controls(P<0.05).No obvious difference was observed in the expression of the other 7 miRNAs between the TOF patients and controls(P>0.05).No meaningful sequence variation was detected in the putative miR1/206 binding sites in the 3'UTR of Cx43.Conclusions:This study indicated that miR-1 and 206 is down-regulated in TOF patients,which may cause an up-regulation of Cx43 protein's synthesis.It provided a clue that miR-1 and 206 might be involved in the pathogenesis of TOF,additional experiments are needed to determine if in fact,miR-1 and 206 contribute substantially to TOF.

Potential association of long noncoding RNA HA117 with tetralogy of Fallot

Tetralogy of Fallot(TOF)is a congenital heart disease characterized by abnormal cardiomyocyte differentiation in the right ventricular outflow tract(RVOT),and HA117 is a novel long noncoding RNA(lncRNA)with anti-differentiation roles.To investigate the potential association of HA117 with TOF,we collected 84 RVOT tissues from patients with TOF.We determined the expression of HA117 in RVOT samples from TOF patients and collected clinical data to conduct a cross-sectional and short-term follow-up study.McGoon ratio,Nakata index,and left ventricular end-diastolic volume index(LVEDVI)were negatively correlated with the expression of HA117 based on subgroup analysis,correlation analysis and logistic regression analysis.Additionally,cardiopulmonary bypass(CPB)time and ICU stay were longer in patients with higher expression of HA117 than in patients with lower expression of HA117.Furthermore,percentage improvement in SPO2 was significantly reduced in patients with increased HA117 expression at 6 months after surgery.Our results suggested that the increased expression of the novel lncRNA HA117 is a risk factor for unfavorable McGoon ratio,Nakata index and LVEDVI in TOF patients.Additionally,an increased expression of HA117 might lead to adverse short-term outcomes in TOF patients.

HIRA Gene is Lower Expressed in the Myocardium of Patients with Tetralogy of Fallot

Background：The most typical cardiac abnormality is conotruncal defects （CTDs） in patients with 22q11 deletion syndrome （22q11DS）.HIRA （histone cell cycle regulator） gene,as one of the candidate genes located at the critical region of 22q11DS,was reported as possibly relevant to CTD in animal models.This study aimed to analyze the level of expression of the HIRA gene in tetralogy of Fallot （TOF） patients and the potential DNA sequence variations in the promoter region.Methods：The messenger RNA （mRNA） expression was examined with quantitative real-time polymerase chain reaction in 39 myocardial tissues of the right ventricular outflow tract （RVOT） from TOF patients and 4 myocardial tissues of RVOT from noncardiac death children.The protein expression was detected using immunohistochemistry in 12 TOF patients and 4 controls.A total of 100 TOF cases and 200 healthy controls were recruited for DNA sequencing.Results：The mRNA and protein expressions of the HIRA gene in the myocardium of the TOF patients were both significantly lower as compared to the controls （P 〈 0.05）.Five single nucleotide polymorphisms （SNPs）,including g.4111A〉G （rs1128399）,g.4265C〉A （rs4585115）,g.4369T〉G （rs2277837）,g.4371C〉A （rs148516780）,and g.4543T〉C （rs111802956）,were found in the promoter region of the HIRA gene.There were no significant differences of frequencies in these SNPs between the TOF patients and the controls （P 〉 0.05）.Conclusion：The abnormal lower expression of the HIRA gene in the myocardium may participate in the pathogenesis of TOF.

Decreased expression of neurotrophic tyrosine receptor kinase 3 is associated with the outflow tract defect of human tetralogy of Fallot

Background The molecular mechanism of human tetralogy of Fallot （TOF） is incompletely defined. Animal models have suggested that neurotrophic tyrosine receptor kinase 3 （NTRK3） might be associated with the outflow tract defect, similar to that seen in human TOF, however, the expression pattern of NTRK3 in human TOF heart tissues has never been investigated. Methods Quantitative real-time PCR （qRT-PCR） and immunohistochemistry were applied to detect NTRK3 mRNA and protein levels in right ventricular outflow tract tissue samples of TOF patients, ventricular septal defect （VSD） patients and normal control infants （n=10 in each group）. Results qRT-PCR analysis indicated that NTRK3 mRNA levels were significantly decreased in the TOF group compared to the VSD group （0.024±0.003 vs 0.085±0.004, P=0.022） and the normal control group （0.024±0.003 vs 0.091±0.002, P=0.006）. Quantitative immunohistochemical analysis showed that NTRK3 protein was mainly localized in the myocardium cytoplasm in all 3 groups. The immunoreactivity of NTRK3 protein was again significantly lower in the TOF group compared to the VSD group （1.42±0.62 vs 14.12±1.83, P=0.023） and the control group （1.42±0.62 vs 16.25±2.31, P=-0.008）. The expression of NTRK3 in the VSD group and in the control group showed no significant differences at both mRNA and protein levels. Conclusions Insufficient expression of NTRK3 is associated with the outflow tract defect of human tetralogy of Fallot and may contribute to the progression of this defect. Chin Med J 2009; 122（2）： 153-157