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The importance of microRNAs for maintaining stability in the developing vertebrate heart has recently become apparent. In addition, there is a growing appreciation for the significance of microRNAs in developmental pathology, including the formation of congenital heart defects. We examined the expression of microRNAs in right ventricular (RV) myocardium from infants with idiopathic tetralogy of Fallot (TOF, without a 22q11.2 deletion), and found 61 microRNAs to be significantly changed in expression in myocardium from children with TOF compared to normally developing comparison subjects (O'Brien et al. 2012). Predicted targets of microRNAs with altered expression were enriched for gene networks that regulate cardiac development. We previously derived a list of 229 genes known to be critical to heart development, and found 44 had significantly changed expression in TOF myocardium relative to normally developing myocardium. These 44 genes had significant negative correlations with 33 microRNAs, each of which also had significantly changed expression. Here, we focus on miR-421, as it is significantly upregulated in RV tissue from infants with TOF; is predicted to interact with multiple members of cardiovascular regulatory pathways; and has been shown to regulate cell proliferation. We knocked down, and over expressed miR-421 in primary cells derived from the RV of infants with TOF, and infants with normally developing hearts, respectively. We found a significant inverse correlation between the expression of miR-421 and SOX4, a key regulator of the Notch pathway, which has been shown to be important for the cardiac outflow track. These findings suggest that the dysregulation of miR-421 warrants further investigation as a potential contributor to tetralogy of Fallot.
Tetralogy of Fallot (TOF) is the most prevalent cyanotic congenital heart pathology and causes infant morbidity and mortality worldwide. GATA-binding protein 4 (GATA4) serves as a pivotal transcriptional factor for embryonic cardiogenesis and germline GATA4 mutations are causally linked to TOF. However, the effects of somatic GATA4 mutations on the pathogenesis of TOF remain to be ascertained. In the present study, sequencing assay of GATA4 was performed utilizing genomic DNA derived from resected heart tissue specimens as well as matched peripheral blood specimens of 62 patients with non-familial TOF who underwent surgical treatment for TOF. Sequencing of GATA4 was also performed using the heart tissue specimens as well as matched peripheral venous blood samples of 68 sporadic cases who underwent heart valve displacement because of rheumatic heart disorder and the peripheral venous whole blood samples of 216 healthy subjects. The function of the mutant was explored by dual-luciferase activity analysis. Consequently, a new GATA4 mutation, NM_002052.5:c.708T>G;p.(Tyr236*), was found in the heart tissue of one patient with TOF. No mutation was detected in the heart tissue of the 68 cases suffering from rheumatic heart disorder or in the venous blood samples of all 346 individuals. GATA4 mutant failed to transactivate its target gene, myosin heavy chain 6. Additionally, this mutation nullified the synergistic transactivation between GATA4 and T-box transcription factor 5 or NK2 homeobox 5, two genes causative for TOF. Somatic GATA4 mutation predisposes TOF, highlighting the significant contribution of somatic variations to the molecular pathogenesis underpinning TOF.
Small RNAs, especially the microRNAs, have been revealed to play great roles in heart development and congenital heart defects. Several studies have shown dysregulated miRNAs in ventricular tissues of Tetralogy of Fallot (TOF) patients. In the present study, we conducted high throughput sequencing to obtain the global profiling of small RNA transcriptome in heart right ventricular samples from 10 age -matched TOF patients. These samples showed dominant composition of miRNA and mitochondrial associated RNAs. By sRNA cluster identification and differential gene expression analysis, significant sexual difference was discovered for sRNA expression in TOF patients. miR-1/miR-133, which have been identified as essential for cardiac development, account for the most variance of sRNA expression between sexes in TOF hearts.
Tetraology of Fallot (TOF) is the most common form of cyanotic congenital heart disease and is a major cause of significant morbidity and mortality. Emerging evidence demonstrates that genetic risk factors are involved in the pathogenesis of TOF. However, TOF is genetically heterogeneous and the genetic defects responsible for TOF remain largely unclear. In the present study, the whole coding region of the GATA5 gene, which encodes a zinc-finger transcription factor essential for cardiogenesis, was sequenced in 130 unrelated patients with TOF. The relatives of the index patients harboring the identified mutations and 200 unrelated control individuals were subsequently genotyped. The functional characteristics of the mutations were analyzed using a luciferase reporter assay system. As a result, 2 novel heterozygous GATA5 mutations, p.R187G and p.H207R, were identified in 2 families with autosomal dominantly inherited TOF, respectively. The variations were absent in 400 control alleles and the altered amino acids were completely conserved evolutionarily. Functional analysis showed that the GATA5 mutants were associated with significantly decreased transcriptional activation compared with their wild-type counterpart. To our knowledge, this is the first report on the association of GATA5 loss-of-function mutations with TOF, suggesting potential implications for the early prophylaxis and allele-specific therapy of human TOF.
To explore the underlying pathogenesis and provide references for genetic counseling and prenatal gene diagnosis, we analyzed the chromosome karyotypes and genome-wide copy number variations (CNVs) in 86 patients with tetralogy of Fallot (TOF) by G-banding karyotype analysis and array-comparative genomic hybridization (aCGH), respectively. And then quantitative polymerase chain reaction was used to validate these candidate CNVs. Based on their different properties, CNVs were categorized into benign CNVs, suspiciously pathogenic CNVs, and indefinite CNVs. Data analysis was based on public databases such as UCSC, DECIPHER, DGV, ISCA, and OMIM.The karyotype was normal in all the 86 patients with TOF. CNVs were detected in 11 patients by aCGH and quantitative polymerase chain reaction. Patient no. 0001, 0010, and 0029 had 2.52-Mb deletion in the chromosome 22q11.21 region; patient no. 0008 had both 595- and 428-kb duplications, respectively, in 12p12.3p12.2 and 14q23.2q23.3 regions; patient no. 0009 had 1.46-Mb duplication in the 1q21.1q21.2 region; patient no. 0016 had 513-kb duplication in the 1q42.13 region; patient no. 0024 had 292-kb duplication in the 16q11.2 region; patient no. 0026 had 270-kb duplication in the 16q24.1 region; patient no. 0028 had 222-kb deletion in the 7q31.1 region; patient no. 0033 had 1.73-Mb duplication in the 17q12 region; and patient no. 0061 had 5.79-Mb deletion in the 1p36.33p36.31 region.aCGH can accurately detect CNVs in the patients with TOF. This is conducive to genetic counseling and prenatal diagnosis for TOF and provides a new clue and theoretical basis for exploring the pathogenesis of congenital heart disease.
The aim of the present study was to identify key genes that may be involved in the pathogenesis of Tetralogy of Fallot (TOF) using bioinformatics methods. The GSE26125 microarray dataset, which includes cardiovascular tissue samples derived from 16 children with TOF and five healthy age‑matched control infants, was downloaded from the Gene Expression Omnibus database. Differential expression analysis was performed between TOF and control samples to identify differentially expressed genes (DEGs) using Student's t‑test, and the R/limma package, with a log2 fold‑change of >2 and a false discovery rate of <0.01 set as thresholds. The biological functions of DEGs were analyzed using the ToppGene database. The ReactomeFIViz application was used to construct functional interaction (FI) networks, and the genes in each module were subjected to pathway enrichment analysis. The iRegulon plugin was used to identify transcription factors predicted to regulate the DEGs in the FI network, and the gene‑transcription factor pairs were then visualized using Cytoscape software. A total of 878 DEGs were identified, including 848 upregulated genes and 30 downregulated genes. The gene FI network contained seven function modules, which were all comprised of upregulated genes. Genes enriched in Module 1 were enriched in the following three neurological disorder‑associated signaling pathways: Parkinson's disease, Alzheimer's disease and Huntington's disease. Genes in Modules 0, 3 and 5 were dominantly enriched in pathways associated with ribosomes and protein translation. The Xbox binding protein 1 transcription factor was demonstrated to be involved in the regulation of genes encoding the subunits of cytoplasmic and mitochondrial ribosomes, as well as genes involved in neurodegenerative disorders. Therefore, dysfunction of genes involved in signaling pathways associated with neurodegenerative disorders, ribosome function and protein translation may contribute to the pathogenesis of TOF.
Gut microbiota plays an important role in cardiovascular health and disease, including congenital heart disease (CHD). Tetralogy of Fallot (TOF) is the most common form of cyanotic CHD characterized by systemic chronic hypoxia and sustained pressure overload of the right ventricle. It is well-known that hypoxia and pressure overload can affect gut microbiota. However, the effects of TOF on the gut microbiota remain little understood. This study explored the profile of the gut microbiota in children with unrepaired TOF.
Rare variants in certain transcription factors involved in cardiac development cause Mendelian forms of congenital heart disease. The purpose of this study was to systematically assess the frequency of rare transcription factor variants in sporadic patients with the cardiac outflow tract malformation tetralogy of Fallot (TOF).
Background Right ventricular outflow tract (RVOT) stenosis after repair of tetralogy of Fallot has been linked with favorable right ventricular remodeling but adverse outcomes. The aim of our study was to assess the hemodynamic impact and prognostic relevance of right ventricular pressure load in this population. Methods and Results A total of 296 patients with repaired tetralogy of Fallot (mean age, 17.8±7.9 years) were included in a prospective cardiovascular magnetic resonance multicenter study. Myocardial strain was quantified by feature tracking technique at study entry. Follow-up, including the need for pulmonary valve replacement, was assessed. The combined end point consisted of ventricular tachycardia and cardiac death. A higher echocardiographic RVOT peak gradient was significantly associated with smaller right ventricular volumes and less pulmonary regurgitation, but lower biventricular longitudinal strain. During a follow-up of 10.1 (0.1-12.9) years, the primary end point was reached in 19 of 296 patients (cardiac death, n=6; sustained ventricular tachycardia, n=2; and nonsustained ventricular tachycardia, n=11). A higher RVOT gradient was associated with the combined outcome (hazard ratio [HR], 1.03; 95% CI, 1.00-1.06; P=0.026), and a cutoff gradient of ≥25 mm Hg was predictive for cardiovascular events (HR, 3.69; 95% CI, 1.47-9.27; P=0.005). In patients with pulmonary regurgitation ≥25%, a mild residual RVOT gradient (15-30 mm Hg) was not associated with a lower risk for pulmonary valve replacement. Conclusions Higher RVOT gradients were associated with less pulmonary regurgitation and smaller right ventricular dimensions but were related to reduced biventricular strain and emerged as univariate predictors of adverse events. Mild residual pressure gradients did not protect from pulmonary valve replacement. These results may have implications for the indication for RVOT reintervention in this population.
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.
Congenital heart disease (CHD) is the most prevalent developmental abnormality in humans and is the most common non-infectious cause of infant morbidity and mortality. Increasing evidence demonstrates that genetic defects are involved in the pathogenesis of CHD. However, CHD is genetically heterogeneous, and the genetic determinants underpinning CHD in most patients remain unknown. In this study, the whole coding region of the PITX2 gene (isoform c) was sequenced in 185 unrelated patients with CHD. The available relatives of a mutation carrier and 300 unrelated healthy individuals used as controls were also genotyped for PITX2. The functional characteristics of the mutation were delineated by using a dual-luciferase reporter assay system. As a result, a novel heterozygous PITX2 mutation, p.Q102L, was identified in a patient with tetralogy of Fallot (TOF). Genetic analysis of the index patient's pedigree showed that the mutation co-segregated with TOF. The mutation was absent in 600 reference chromosomes. Biochemical analysis revealed that the Q102L-mutant PITX2 is associated with significantly reduced transcriptional activity compared with its wild-type counterpart. Furthermore, the mutation markedly decreased the synergistic activation between PITX2 and NKX2-5. This study firstly associates PITX2 loss-of-function mutation with increased susceptibility to TOF, providing novel insight into the molecular mechanism of CHD.
The impact of congenital heart disease on brain aging has not been extensively investigated. We evaluated cerebral microbleeds and white matter hyperintensities on brain magnetic resonance imaging in adult patients with tetralogy of Fallot (ToF). Ten ToF patients (6 women, 4 men; aged 21-58 years; New York Heart Association [NYHA] class 1-2) were prospectively enrolled and underwent a T1-weighted, a T2-weighted dark fluid, and a T2*-weighted scans. Ten age- and sex-matched controls were prospectively recruited and subjected to the same acquisition protocol. Cerebral microbleeds (CMBs) were manually counted while white matter hyperintensities (WMHs) were segmented using ITK-Snap. Wilcoxon signed-rank test, Spearman correlation, and Bland-Altman statistics were used. The median (interquartile range [IQR]) age was 45.0 (30.5-49.5) years in ToF patients and 46.0 (30.5-49.8) years in controls. The median (IQR) of the number of CMBs was 6.0 (4.0-7.8) in ToF patients and 0 (0.0-0.0) in controls (p = 0.002). The WMHs burden was 2,506 (1,557-2,900) mm3 for ToF patients and 2,212 (1,860-2,586) mm3 for controls (p = 0.160). Moreover, a positive significant correlation was found between the WMHs burden and the NYHA class (ρ = 0.80, p = 0.005). Inter-operator concordance rate for the presence/absence of CMBs was 90%; the reproducibility for the WMHs burden was 77%. In conclusion, we found more cerebral microbleeds and a higher WMHs burden in adult ToF patients than in controls. This preliminary comparison supports the hypothesis of an early brain aging in ToF patients. Larger studies are warranted.
Background Increased aortic wall stiffness, which even persists after repair, has been reported in patients with tetralogy of Fallot (TOF). We aimed to observe the distensibility of the ascending aorta and descending aorta in fetuses with TOF and explore its relation with aortic blood flow volume and aortic and pulmonary annular size. Methods and Results Twenty-three fetuses with TOF and 23 gestational age-matched normal fetuses were included in this prospective cross-sectional study. The distensibilities of the ascending aorta and descending aorta were assessed by aortic strain (AS), which was defined as follows: 100×(maximum internal diameter in the systolic phase-minimum internal diameter in the diastolic phase)/minimum internal diameter in the diastolic phase. The maximum internal diameter in the systolic phase and minimum internal diameter in the diastolic phase of the ascending aorta and descending aorta were measured by M-mode echocardiography. Associations between AS and aortic blood flow volume and aortic and pulmonary valve diameters were assessed in both groups. AS of the ascending aorta in TOF group was lower than that in controls (20.48%±4.19% versus 28.17%±4.54%; P<0.001), whereas there was no significant difference in the descending aorta. The multivariate regression model demonstrated that AS was significantly related to aortic valve size (P=0.014) and aortic blood flow volume (P=0.022) in fetuses with TOF, whereas only aortic blood flow volume was significantly correlated with AS in the control group (P=0.01). No significant association was found between AS and pulmonary valve size. Conclusions Impaired distensibility of proximal aorta was observed in fetuses with TOF. Both intrinsic abnormalities of the aortic wall and aortic volume overload probably play roles in the altered aortic distensibility.
To analyze some morphological aspects of the tetralogy of Fallot which have been raising controversies in the literature, due to the different approach to the nomenclature of congenital heart defects by different authors regarding the definition of double outlet right ventricle and its concomitance with tetralogy.
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