Tetralogy Of Fallot Cases Research Articles

Infective endocarditis in an adult with undiagnosed tetralogy of Fallot: a case report of a rare presentation.

Unrepaired tetralogy of Fallot (TOF) is uncommonly diagnosed in adulthood and only 3% of patients survive to reach the age of 40 without surgical repair. If unrepaired, these patients are at risk for infective endocarditis (IE). In this report, we present a case of a middle-aged, previously healthy female whose only complaint was unexplained fever. Echocardiography led to the discovery of undiagnosed TOF complicated with IE with a vegetation on the right ventricular (RV) side of the ventricular septal defect (VSD) which was appropriately managed with antibiotics. In rare cases of acyanotic TOF where there is a lesser degree of right ventricular outflow tract obstruction (RVOTO), patients may survive into adulthood and can be asymptomatic till becoming initially presented with complications such as infective endocarditis.

Automated biventricular quantification in patients with repaired tetralogy of Fallot using a 3D deep learning segmentation model

BackgroundDeep learning is the state-of-the-art approach for automated segmentation of the left ventricle (LV) and right ventricle (RV) in cardiac magnetic resonance (CMR) images. However, these models have been mostly trained and validated using CMR datasets of structurally normal hearts or cases with acquired cardiac disease, and are therefore not well-suited to handle cases with congenital cardiac disease such as tetralogy of Fallot (TOF). We aimed to develop and validate a dedicated model with improved performance for LV and RV cavity and myocardium quantification in patients with repaired TOF. MethodsWe trained a 3D convolutional neural network (CNN) with 5-fold cross-validation using manually delineated end-diastolic (ED) and end-systolic (ES) short-axis image stacks obtained from either a public dataset containing patients with no or acquired cardiac pathology (n=100), an institutional dataset of TOF patients (n=96), or both datasets mixed. Our method allows for missing labels in the training images to accommodate for different ED and ES phases for LV and RV as is commonly the case in TOF. The best performing model was applied to all frames of a separate test set of TOF cases (n=36) and ED and ES phases were automatically determined for LV and RV separately. The model was evaluated against the performance of a commercial software (suiteHEART®, NeoSoft, Pewaukee, Wisconsin, US). ResultsTraining on the mixture of both datasets yielded the best agreement with the manual ground truth for the TOF cases, achieving a median DICE similarity coefficient of (93.8%, 89.8%) for LV cavity and of (92.9%, 90.9%) for RV cavity at (ED, ES) respectively, and of 80.9% and 61.8% for LV and RV myocardium at ED. The offset in automated ED and ES frame selection was 0.56 and 0.89 frames on average for LV and RV respectively. No statistically significant differences were found between our model and the commercial software for LV quantification (two-sided Wilcoxon signed rank test, p<5%), while RV quantification was significantly improved with our model achieving a mean absolute error of 12ml for RV cavity compared to 36ml for the commercial software. ConclusionWe developed and validated a fully automatic segmentation and quantification approach for LV and RV, including RV mass, in patients with repaired TOF. Compared to a commercial software, our approach is superior for RV quantification indicating its potential in clinical practice.

Total Correction for Tetralogy of Fallot in Patients Weighing Over 10 kg: Experiences and Follow-Up Outcomes.

Background Although the recommended time for total correction of tetralogy of Fallot (TOF) is during infancy, sometimes TOF cases present to healthcare setups after pre-school age, with some cases presenting even beyond adolescence in developing countries. The objective of this study was to assess patients with TOF weighing 10 kg and above who underwent definitive corrective surgical techniques such as transannular patch (TAP), valve-sparing right ventricular outflow tract (RVOT) pericardial patch augmentation, non-ventriculotomy infundibular resection for postoperative complications, hospital stay, and right ventricular (RV) dysfunction in the immediate postoperative period and subsequent outpatient department follow-ups. Methodology This comprehensive, retrospective cohort study included single-center data collected between January 16, 2018, and January 15, 2024. The study included 63 patients diagnosed with TOF weighing 10 kg and above, ensuring a robust and representative sample. Results Of the 119 patients who underwent total correction for TOF, 63 met the study's inclusion criteria of TOF weighing above 10 kg. Of the 63 patients, 55.6% were males, and 44.4% were females.The mean weight of the study participants was 33.4 kg. The mean age was 15.9 years. Of the 63 patients, 39 underwent TAP surgery, 18 underwent RVOT patch augmentation, and six underwent total correction by non-ventriculotomy infundibular resection. There was a significant difference between the type of surgery groups and RV dysfunction, with the TAP group showing a higher incidence of RV dysfunction, indicating a potential risk factor associated with this technique. Conclusions Although TAP has significant immediate postoperative complications compared to other techniques, its long-term follow-up suggests that long-term survival and quality of life, as measured by major adverse cardiac events such as heart failure, arrhythmias, and reoperation rates, are commensurable in adulthood. This indicates that despite the initial challenges, TAP can provide satisfactory outcomes in the long run.

Integration of case-based learning and three-dimensional printing for tetralogy of fallot instruction in clinical medical undergraduates: a randomized controlled trial

BackgroundCase-based learning (CBL) methods have gained prominence in medical education, proving especially effective for preclinical training in undergraduate medical education. Tetralogy of Fallot (TOF) is a congenital heart disease characterized by four malformations, presenting a challenge in medical education due to the complexity of its anatomical pathology. Three-dimensional printing (3DP), generating physical replicas from data, offers a valuable tool for illustrating intricate anatomical structures and spatial relationships in the classroom. This study explores the integration of 3DP with CBL teaching for clinical medical undergraduates.MethodsSixty senior clinical medical undergraduates were randomly assigned to the CBL group and the CBL-3DP group. Computed tomography imaging data from a typical TOF case were exported, processed, and utilized to create four TOF models with a color 3D printer. The CBL group employed CBL teaching methods, while the CBL-3DP group combined CBL with 3D-printed models. Post-class exams and questionnaires assessed the teaching effectiveness of both groups.ResultsThe CBL-3DP group exhibited improved performance in post-class examinations, particularly in pathological anatomy and TOF imaging data analysis (P < 0.05). Questionnaire responses from the CBL-3DP group indicated enhanced satisfaction with teaching mode, promotion of diagnostic skills, bolstering of self-assurance in managing TOF cases, and cultivation of critical thinking and clinical reasoning abilities (P < 0.05). These findings underscore the potential of 3D printed models to augment the effectiveness of CBL, aiding students in mastering instructional content and bolstering their interest and self-confidence in learning.ConclusionThe fusion of CBL with 3D printing models is feasible and effective in TOF instruction to clinical medical undergraduates, and worthy of popularization and application in medical education, especially for courses involving intricate anatomical components.

Human Genetics of Tetralogy of Fallot and Double-Outlet Right Ventricle.

Tetralogy of Fallot (TOF) and double-outlet right ventricle (DORV) are conotruncal defects resulting from disturbances of the second heart field and the neural crest, which can occur as isolated malformations or as part of multiorgan syndromes. Their etiology is multifactorial and characterized by overlapping genetic causes. In this chapter, we present the different genetic alterations underlying the two diseases, which range from chromosomal abnormalities like aneuploidies and structural mutations to rare singlenucleotide variations affecting distinct genes. For example, mutations in the cardiac transcription factors NKX2-5, GATA4, and HAND2 have been identified in isolated TOF cases, while mutations of TBX5 and 22q11 deletion, leading to haploinsufficiency of TBX1, cause Holt-Oram and DiGeorge syndrome, respectively. Moreover, genes involved in signaling pathways, laterality determination, and epigenetic mechanisms have also been found mutated in TOF and/or DORV patients. Finally, genome-wide association studies identified common singlenucleotide polymorphisms associated with the risk for TOF.

An integrated in-vitro and in-silico workflow to study the pulmonary bifurcation hemodynamics

Tetralogy of Fallot (ToF) is the most common congenital heart disease. In this work, hemodynamics of pulmonary arteries (PA) in ToF patients was investigated using patient-specific image-based models. The study included the investigation of right and left pulmonary arteries (RPA and LPA, respectively). Numerical and experimental tools were used to reliably model the patient-specific fluid dynamics, including the pathological features present in ToF cases, i.e. regurgitation, hypertensive pressure and asymmetric right/left flow split. A genetic algorithm (GA) was developed to estimate two sets of patient-specific RCR values, according to the RPA–LPA flow split and pressure range of the subject. GA outcomes were validated using experimental and computational fluid dynamics (CFD) simulations. A mock loop circuit was set up including a 3D printed phantom of a representative pathological PA. The experiment was replicated with a CFD simulation. Both in-vitro and in-silico results showed very good agreement, with relative errors below 10%, with the prediction of the GA, demonstrating that the computed RCR values were suitable to provide the correct flow split and pressure range in ToF patients. In this study we present an image-based method with a custom GA algorithm for the estimation of patient-specific RCR parameters for a ToF PA bifurcation, taking into account the patient’s flow split of the subject. This approach is promising for further modeling of PA pathologies thus facilitating the translation of patient-specific simulations in clinics.

Prenatal diagnosis of tetralogy of Fallot with an absent pulmonary valve: is this malformation still associated with a poor prognosis? A 5-year single-center experience

Objective: This study sought to assess the prenatal features and clinical outcomes of cases with a fetal diagnosis of tetralogy of Fallot (TOF) with an absent pulmonary valve (APV) at our maternal-fetal medicine unit. Methods: Twelve cases of TOF and APV prenatally diagnosed at Kanuni Sultan Süleyman Training and Research Hospital between 2015 and 2020 were retrospectively reviewed. Prenatal characteristics, additional cardiac and extracardiac anomalies, and postnatal outcomes of the cases were examined. Results: The median gestational age at diagnosis was 22 weeks (range: 18–24 weeks). The absence of ductus arteriosus was found in all cases (100%). Karyotype analysis was performed in 5 cases. A chromosomal abnormality was detected in 3 of these cases (60%); 2 cases with 22q11 microdeletion, and 1 case with trisomy 21. Parents opted for termination of pregnancy in two of these cases; 1 case with 22q11 microdeletion, and 1 case with trisomy 21. Two patients experienced spontaneous intrauterine fetal demise. Finally, 8 live-born fetuses underwent total correction surgery during the postnatal period. Four (33.3%) out of 12 cases survived at the end of the 4-years follow-up period. Conclusion: While TOF with APV cases were predominantly associated with poor prognoses in the past, more promising results have been obtained in recent years in parallel with the developments in surgery and postnatal care. For this reason, we think that the prognosis will be even better in the coming years as the developments in surgical technique and care continue.

IMMEDIATE AND EARLY OUTCOME OF PULMONARY VALVE CUSP AUGMENTATION FOR REPAIR OF TETRALOGY OF FALLOT (TOF)

Objectives: To determine the immediate and early outcome of pulmonary valve cusp augmentation for repair of tetralogy of Fallot (TOF)&#x0D; Methods: A descriptive study of 36 cases of TOF repair done from July 2020 to December 2022 at Faisalabad Institute of cardiology (FIC). Autologous pericardium used in all cases to augment the pulmonary valve cusp to increase the size of pulmonary valve orifice. Patients were followed in immediate and early post operative period by doing echocardiography to observe the outcome including pulmonary valve regurgitation (PR), stenosis and right ventricular outflow tract obstruction (RVOTO)&#x0D; Results: Median age was 12 years (4–21). Immediate Post repair echocardiography showed no PR in 77.8 % of patients (n=28) while 8 patients had mild PR (22.2%). Majority of patients (61.1%) had mild RVOT obstruction, 13 patients (36.1%) had moderate RVOT obstruction while one patient had severe RVOT obstruction. Mean gradient across RVOT was 36.72 (+/- 11.08). The data on most recent follow up showed no PR in 83.3% (n=30) patients, while 6 patients (16.7%) had mild pulmonary regurgitation. Mild RVOTO was seen in 47.2 % of patients (n=17), 50% (n=18) patients had moderate RVOTO while one patient had severe RVOTO. Mean RVOT gradient was 40.8 +/- 15.20. There was no statistically significant difference between immediate and at last follow up RVOT gradient (p-value = 0.119)&#x0D; Conclusion: Augmentation of the pulmonary valve cusp in selective cases of TOF is a useful technique to avoid the need of transannular patch in significant number of cases&#x0D; Keywords: Tetralogy of Fallot, right ventricular outflow tract, cusp augmentation, transannular.&#x0D;

Electroencephalographic changes in neurologically free patients with tetralogy of Fallot after surgical repair: a cross section study in Egyptian children

BackgroundSurgical correction of tetralogy of Fallot (TOF) is still one of the most frequently performed intervention in pediatric cardiac surgery. The occurrence of seizures after repair or palliation of congenital heart disease (CHD) is a marker for a central nervous system (CNS) injury and has been associated with adverse neurodevelopmental sequelae. The prognostic value of electroencephalogram (EEG) for outcome prediction is glowing in children with CHD undergoing open-heart surgery who are at risk for subsequent neurodevelopmental deficits. To our knowledge, this is the first study to detect the EEG changes in neurologically free TOF patients after surgical repairResultsOur study included 68 TOF cases and 32 sex- and age-matched control group; they were 66.0% males and 34.0% females. The mean age of the studied children was 11.41 ± 4.23 years. There was statistically significant difference between TOF patients and control group as regards alpha power and Delta% in left occipital region and Alpha% in right occipital region, with dominant alpha waves in patients’ right occipital region. None of our patients had epileptic waves. The duration after operation showed negative correlation with Delta% at left occipital region and positive correlation with Alpha% in right occipital region (p = 0.002, p = 0.044 respectively).ConclusionTOF cases showed changes in EEG parameters chiefly dominant alpha power and Delta% in left occipital region and dominant Alpha% in right occipital region. Duration after surgery correlated negatively with Delta% at left occipital region, and positively with Alpha% in the right occipital region. Subsequent assessment is recommended to study long-term hazards of these varied dominance of EEG waves in our patients, e.g., evaluation of the cognitive functions.

Predictive value of fetal echocardiographic parameters in surgical strategy for Tetralogy of Fallot.

This study aimed to evaluate whether fetal echocardiographic parameters were predictive of the postnatal surgical treatment required for fetuses with Tetralogy of Fallot (TOF). The fetal echocardiographic and postnatal clinical data of all cases of prenatal TOF at Xinhua Hospital from 2016 to 2020 were reviewed. Patients were categorized based on the operation type, and cardiac parameters were compared between groups. Of the 37 fetuses assessed, the development of the pulmonary valve annulus (PVA) was significantly poorer in the transannular patch group. Patients with a prenatal PVA z-score (Schneider's method) ≥ -2.645, a PVA z-score (Lee's method) ≥ -2.805, a PVA/aortic valve annulus diameter ratio ≥.697, and a pulmonary annulus index ≥ .823 were more likely to undergo pulmonary valve-sparing surgery. There was a strong correlation between prenatal and postnatal PVA z-scores. The PVA growth potential was greater in the pulmonary valve-sparing surgery group. PVA-related parameters evaluated by fetal echocardiography can predict the type of surgical intervention required and are valuable in improving prenatal counseling in fetal cases of TOF.

Genetic insights into non-syndromic Tetralogy of Fallot.

Congenital heart defects (CHD) include structural abnormalities of the heart or/and great vessels that are present at birth. CHD affects around 1% of all newborns worldwide. Tetralogy of Fallot (TOF) is the most prevalent cyanotic congenital cardiac abnormality, affecting three out of every 10,000 live infants with a prevalence rate of 5–10% of all congenital cardiac defects. The four hallmark characteristics of TOF are: right ventricular hypertrophy, pulmonary stenosis, ventricular septal defect, and overriding aorta. Approximately 20% of cases of TOF are associated with a known disease or chromosomal abnormality, with the remaining 80% of TOF cases being non-syndromic, with no known aetiology. Relatively few TOF patients have been studied, and little is known about critical causative genes for non-syndromic TOF. However, rare genetic variants have been identified as significant risk factors for CHD, and are likely to cause some cases of TOF. Therefore, this review aims to provide an update on well-characterized genes and the most recent variants identified for non-syndromic TOF.

Unilateral absence of pulmonary artery with absent pulmonary valve in tetralogy of Fallot.

The incidence of absent pulmonary valve (APV) in tetralogy of Fallot is 2.4 to 6.3%. About 1-3% of the patients with tetralogy of Fallot will have unilateral absence of pulmonary artery (UAPA). However, coexistence of APV with tetralogy of Fallot (TOF) and UAPA is extremely rare. This rare subset can present in two forms. In one group, the main pulmonary artery continues as either left or right pulmonary artery (UAPA) and there is true absence of contralateral pulmonary artery. The second group is termed as unilateral anomalous origin of pulmonary artery (UAOPA), in which the contralateral lung is supplied either by patent ductus arteriosus or a collateral from the aorta. There are a limited number of these cases in the literature. We present a rare case of TOF with APV and UAPA managed using a different surgical technique. Also, we have done contemporary literature review.

Echocardiographic findings in patients with tetralogy of fallot prior to total corrective surgery admitted at a tertiary care hospital.

Objective: To find out echocardiographic findings in patients with tetralogy of Fallot (TOF) prior to total corrective surgery admitted at a tertiary care hospital. Study Design: Cross-sectional study. Setting: Department of Pediatric Cardiology, National Institute of Cardiovascular Disease, Karachi. Period: January 2021 to December 2021. Material &amp; Methods: A total of 197 echocardiography confirmed TOF cases of both genders and age up to any years were included. Physical examination, chest radiography and electrocardiogram were done in each patient prior to transthoracic echocardiography (TTE) using Toshiba Aplio i600 using 5 Hz and 6 Hz transducers. Standard protocols were followed in all TTE procedures. Results: In a total of 197 patients with TOF, there were 121 (61.4%) male. Mean age was 8.36±10.12 years. Hypoplastic pulmonary arteries was the most frequent pulmonary artery abnormality observed in 30 (15.2%) cases. Thickened and domed pulmonic valve was the most common pulmonary valvular anomaly noted in 89 (45.2%). Associated “atrial septal defect (ASD)” was observed in 47 (23.9%) cases while “patent ductus arteriosus (PDA)” was seen in 83 (42.1%) patients. History of past “Blalock and Taussig (BT) Shunt” performed was found in 20 (10.2%) cases, out of which, 15 were functioning. Conclusion: Echocardiography is an inexpensive and safe approach to cardiac evaluation among patients of tetralogy of fallot. Hypoplastic pulmonary arteries was the most frequent pulmonary artery abnormality observed in tetralogy of Fallot patients. PDA was the most frequent associated abnormality followed by associated ASD.

Prenatal Diagnosis, Associations and Outcome for Fetuses with Congenital Absence of the Pulmonary Valve Syndrome.

Background:The aim of this study is to review the spectrum of the prenatally detected absent pulmonary valve syndrome and its outcome after diagnosis.Methods:Clinical data and echocardiographic findings of 37 cases with a fetal diagnosis of absent pulmonary valve syndrome between 2008 and 2020 were analyzed in this retrospective multicenter study.Results:Median gestational age at diagnosis was 25 weeks. Three subtypes of absent pulmonary valve syndrome were observed: (1) with tetralogy of Fallot (n = 30; 81.0%); (2) absent pulmonary valve syndrome with intact ventricular septum (n = 5; 13.5%); (3) with complete atrioventricular septal defect (n = 2; 5.4%). In contrast to 7/25 fetuses (28%) with tetralogy of Fallot-absent pulmonary valve syndrome who had a patent ductus arteriosus, all 5 fetuses with absent pulmonary valve syndrome-intact ventricular septum had a patent ductus arteriosus (P < .001). No significant difference was found between the z-scores of pulmonary artery branches in fetuses with or without patent ductus arteriosus (P > .05). The analysis did not reveal any correlation between gestational week and z-scores of pulmonary artery, pulmonary artery branches (right pulmonary artery, left pulmonary artery), and ratio of aorta/pulmonary artery ratio. The echocardiographic measurements of survivors did not differ significantly from non-survivors (P > .05). Extracardiac anomalies were observed in 8/37 fetuses (21.6%). The incidence of extracardiac anomaly was significantly higher in cases of tetralogy of Fallot-absent pulmonary valve syndrome (P < .05). Overall, 9 fetuses (24%) had genetic anomalies. All 6 fetuses (20%) with 22q11.2 microdeletion were within the tetralogy of Fallot-absent pulmonary valve syndrome group. Overall survival after initial diagnosis in the total cases was 36.6% (11/30), with 9 of 30 (30%) tetralogy of Fallot-absent pulmonary valve syndrome cases and 2 of 5 (40%) absent pulmonary valve syndrome-intact ventricular septum cases.Conclusions:In this largest series of absent pulmonary valve syndrome, extracardiac, and chromosomal anomalies were found to be a common occurrence. The risk of 22q11.2 microdeletion was higher in tetralogy of Fallot cases at 40%. The sizes of the pulmonary artery and its branches and the aorta had no correlation of high mortality antenatally or after birth, which were 63.4% and 47.7%, respectively.

Identification of novel rare copy number variants associated with sporadic tetralogy of Fallot and clinical implications

Tetralogy of Fallot (TOF) is the most common cyanotic congenital heart disease. Highly penetrant copy number variants (CNVs) and genes related to the etiology of TOF likely exist with differences among populations. We aimed to identify CNV contributions to sporadic TOF cases in Han Chinese. Genomic DNA was extracted from peripheral blood in 605 subjects (303 sporadic TOF and 302 unaffected Han Chinese [Control] from cardiac centers in China) and analyzed by genome-wide association study (GWAS). The GWAS results were compared with existing Database of Genetic Variants. These CNVs were further validated by qPCR. Bioinformatics analyses were performed with protein-protein interaction (PPI) network and KEGG pathway enrichment. Across all chromosomes 119 novel "TOF-specific CNVs" were identified with prevalence of CNVs of 21.5% in chromosomes 1-20 and 37.0% including Chr21/22. In chromosomes 1-20, CNVs on 11q25 (encompasses genes ACAD8, B3GAT1, GLB1L2, GLB1L3, IGSF9B, JAM3, LOC100128239, LOC283177, MIR4697, MIR4697HG, NCAPD3, OPCML, SPATA19, THYN1, and VPS26B) and 14q32.33 (encompasses genes THYN1, OPCML, and NCAPD3) encompass genes most likely to be associated with TOF. Specific CNVs found on the chromosome 21 (6.3%) and 22(11.9%) were also identified in details. PPI network analysis identified the genes covering the specific CNVs related to TOF and the signaling pathways. This study for first time identified novel TOF-specific CNVs in the Han Chinese with higher frequency than in Caucasians and with 11q25 and 14q32.33 not reported in TOF of Caucasians. These novel CNVs identify new candidate genes for TOF and provide new insights into genetic basis of TOF.

Case Report: Tetralogy of Fallot in a Chinese Family Caused by a Novel Missense Variant of MYOM2

BackgroundRare genetic variants have been identified to be important contributors to the risk of Tetralogy of Fallot (TOF), the most common cyanotic congenital heart disease (CHD). But relatively limited familial studies with small numbers of TOF cases have been reported to date. In this study, we aimed to identify novel pathogenic genes and variants that caused TOF in a Chinese family using whole exome sequencing (WES).MethodsA Chinese family whose twins were affected by TOF were recruited for this study. A WES was performed for the affected twins, their healthy brother, and parents to identify the potential pathogenic mutated gene(s). Heterozygous variants carried by the twins, but not the unaffected brother, were retained. Public databases were used to assess the frequencies of the selected variants, and online prediction tools were accessed to predict the influences of these variants on protein function. The final candidate variant was further confirmed by Sanger sequencing in other members of the family.ResultsAfter several filtering processes, a heterozygous missense variant in the MYOM2 gene (NM_003970.4:c.3097C>T:p.R1033C) was identified and confirmed by Sanger sequencing in the affected twins and their unaffected father, suggesting an inheritance pattern with incomplete penetrance. The variant was found to be extremely rare in the public databases. Furthermore, the mutated site was highly conserved among mammals, and as shown using multiple online prediction tools, this variant was predicted to be a detrimental variant.ConclusionWe assessed a family with TOF caused by a rare heterozygous missense variant of MYOM2. Our findings not only further confirm the significant role of genetics in the incidence of TOF but also expand the spectrum of the gene variants that lead to TOF.

Implantation of monocusp valve prolongs the duration of chest tube drainage in children with tetralogy of fallot after corrective surgery.

Right ventricular outflow tract obstruction relief is one of the major procedures during the total correction of tetralogy of Fallot (TOF). Pulmonary insufficiency (PI) is usually inevitable after a transannular incision with a patch repair is performed. Therefore, some surgeons advocate to place a monocusp valve within the transannular patch (TAP) in order to decrease the severity of the PI. However, the monocusp valve seemed not be very effective in some patients who underwent the complete TOF repair. Patients who had the classic form of TOF between January 2009 and January 2017 and underwent the corrective surgery with a TAP by the same cardiovascular surgeon were identified for further analysis. Clinical information including demographics at operation, perioperative data, and postoperative outcome were collected retrospectively and compared between the group with and without a monocusp valve. A total of 24 TOF cases were included in the final analysis, and 16 (66.7%) patients received a monocusp valve placement. The patients' characteristics before and during the surgery were similar between the two groups. The median duration of chest tube drainage after the total correction in the monocusp group was longer than those without the valve (p = 0.04). There was no difference in the immediate postoperative data, including the inflammation/infection status, the duration of mechanical ventilation, and the length of ICU and hospital stay. Implantation of a monocusp valve during the total TOF correction using a TAP did not bring benefit to improve the immediate postoperative outcomes, especially the duration of the pleural drainage. Further study with a prospective design and a larger number of cases is needed.

CpG site hypomethylation at ETS1‑binding region regulates DLK1 expression in Chinese patients with Tetralogy of Fallot.

Tetralogy of Fallot (TOF) is the most common cyanotic congenital heart malformation accounting for ~10% of cases. Although the pathogenesis of TOF is complex and largely unknown, epigenetics plays a huge role, specifically DNA methylation. The protein δ like non-canonical Notch ligand 1 (DLK1) gene encodes a non-canonical ligand of the Notch signaling pathway, which is involved in heart development. However, the epigenetic mechanism of DLK1 in the pathogenesis of TOF is yet to be elucidated. Therefore, the present study aimed to clarify its specific mechanism. In this study, immunohistochemistry was used to detect the protein expression of DLK1 and the methylation status of the DLK1 promoter was measured via bisulfite sequencing PCR. Dual-luciferase reporter assays were performed to examine the influence of transcription factor ETS proto-oncogene 1 (ETS1) on DLK1 gene expression. The electrophoretic mobility shift assay and chromatin immunoprecipitation assay, both in vivo and in vitro, were used to verify the binding of the ETS1 transcription factor to the DLK1 promoter as well as the influence of methylation status of DLK1 promoter on this binding affinity. The expression of DLK1 in the right ventricular outflow tract was significantly lower in patients with Tetralogy of Fallot (TOF) than that in controls (P<0.001). Moreover, the methylation level of CpG site 10 and CpG site 11 in the DLK1_R region was significantly decreased in TOF cases compared with controls (P<0.01). The integral methylation levels of DLK1_R and the methylation status of the CpG site 11 were both positively associated with DLK1 protein expression in TOF cases. ETS1 was found to inhibit DLK1 transcriptional activity by binding to the CpG site 11 and this affinity could be influenced by the methylation level of the DLK1 promoter. These findings demonstrated that the hypomethylation of the DLK1 promoter could increase the binding affinity of ETS1 transcription factor, which in turn inhibited DLK1 gene transcriptional activity and contributed to the development of TOF.

Rare variants in KDR, encoding VEGF Receptor 2, are associated with tetralogy of Fallot

PurposeRare genetic variants in KDR, encoding the vascular endothelial growth factor receptor 2 (VEGFR2), have been reported in patients with tetralogy of Fallot (TOF). However, their role in disease causality and pathogenesis remains unclear. MethodsWe conducted exome sequencing in a familial case of TOF and large-scale genetic studies, including burden testing, in >1,500 patients with TOF. We studied gene-targeted mice and conducted cell-based assays to explore the role of KDR genetic variation in the etiology of TOF. ResultsExome sequencing in a family with two siblings affected by TOF revealed biallelic missense variants in KDR. Studies in knock-in mice and in HEK 293T cells identified embryonic lethality for one variant when occurring in the homozygous state, and a significantly reduced VEGFR2 phosphorylation for both variants. Rare variant burden analysis conducted in a set of 1,569 patients of European descent with TOF identified a 46-fold enrichment of protein-truncating variants (PTVs) in TOF cases compared to controls (P = 7 × 10-11). ConclusionRare KDR variants, in particular PTVs, strongly associate with TOF, likely in the setting of different inheritance patterns. Supported by genetic and in vivo and in vitro functional analysis, we propose loss-of-function of VEGFR2 as one of the mechanisms involved in the pathogenesis of TOF.

Tetralogy of Fallot in a Two-Month-Old Holstein Calf

In this case report, a case of tetralogy of fallot (ToF) in a two-month-old female, Holstein breed calf was described. Following necropsy examination, all tissue samples were collected and fixed in %10 buffer formalin solution, embedded in paraffin, sectioned at 5 µm and stained routinely with Hematoxylin-Eosin. At necropsy, the heart was enlarged; the pericardium was edematous, opaque and was distended with fluid transudate. In the heart, pulmonary stenosis with a diameter of 1.8 cm, a defect (3 cm in diameter) in the cranial of the interventricular septum, dilatation of the right ventricle and thickening of its wall and right displacement of the aorta on the interventricular septum were observed. According to these findings, the present case was diagnosed as ToF. To the best of our knowledge, this case is the first case of ToF in Turkey.