Brugada Syndrome and Pulmonary Atresia with Intact Interventricular Septum: Fortuitous Finding or New Genetic Connection?

Brugada syndrome is a rare arrhythmogenic syndrome associated mainly with pathogenic variants in the SCN5A gene. Right ventricle outflow tract fibrosis has been reported in some cases of patients diagnosed with Brugada syndrome. Pulmonary atresia with an intact ventricular septum is characterized by the lack of a functional pulmonary valve, due to the underdevelopment of the right ventricle outflow tract. We report, for the first time, a 4-year-old boy with pulmonary atresia with an intact ventricular septum who harbored a pathogenic de novo variant in SCN5A, and the ajmaline test unmasked a type-1 Brugada pattern. We suggest that deleterious variants in the SCN5A gene could be implicated in pulmonary atresia with an intact ventricular septum embryogenesis, leading to overlapping phenotypes.

Accuracy of Fetal Echocardiography in Defining Pulmonary Artery Anatomy and Source of Pulmonary Blood flow in Pulmonary Atresia with Ventricular Septal Defect (PA/VSD).

Precise delineation of central and branch pulmonary artery anatomy, patent ductus arteriosus, and major aorto-pulmonary collateral artery anatomy in the fetal diagnosis of pulmonary atresia with ventricular septal defect is challenging but important to prenatal counseling and postnatal management. We aimed to evaluate the accuracy of fetal echocardiography to determine these anatomical nuances in pulmonary atresia with ventricular septal defect. This was a retrospective, single-institution, 10-year chart review of consecutive prenatal diagnosis of pulmonary atresia with ventricular septal defect for assessment of pulmonary artery, patent ductus arteriosus, and major aorto-pulmonary collateral artery anatomy and comparison with postnatal imaging including echocardiography, cardiac catheterization, and computerized tomography angiography. Twenty-six fetuses were diagnosed with pulmonary atresia with ventricular septal defect during the review period and complete postnatal follow-up was available in 18, all confirming the basic prenatal diagnosis. Fetal echocardiography accurately predicted central and branch pulmonary artery anatomy in 16 (89%) [confluent in 14, discontinuous in 2], patent ductus arteriosus status in 15 (83%) [present in 10, absent in 5], and major aorto-pulmonary collateral arteries in 17 (94%) [present in 9, absent in 8]. Accuracy increased to 100% for pulmonary artery anatomy (16/16) and major aorto-pulmonary collateral artery (17/17) when excluding patients whose anatomy was reported as uncertain on fetal echocardiography. Fetal echocardiography can provide accurate anatomical details in the vast majority of fetuses with pulmonary atresia with ventricular septal defect. This allows for more anatomy-specific counseling, prognostication, and improved selection of postnatally available management options.

A loss-of-function mutation p.T256M in NDRG4 is implicated in the pathogenesis of pulmonary atresia with ventricular septal defect (PA/VSD) and tetralogy of Fallot (TOF).

Pulmonary atresia with ventricular septal defect (PA/VSD) is a rare congenital heart disease (CHD) characterized by a lack of luminal continuity and blood flow from either the right ventricle or the pulmonary artery, together with VSDs. The prevalence of PA/VSD is about 0.2% of live births and approximately 2% of CHDs. PA/VSD is similar to tetralogy of Fallot (TOF) in terms of structural and pathological characteristics. The pathogenesis of these two CHDs remains incompletely understood. It was previously reported that N-myc downstream-regulated gene (NDRG)4 is required for myocyte proliferation during early cardiac development. In the present study, we enrolled 80 unrelated patients with PA/VSD or TOF and identified a probably damaging variant p.T256M of NDRG4. The p.T256M variant impaired the proliferation ability of human cardiac myocytes (hCM). Furthermore, the p.T256M variant resulted in G1 and G2 arrest of hCM, followed by an increase in p27 and caspase-9 expression. Our results provide evidence that the p.T256M variant in NDRG4 is a pathogenic variant associated with impaired hCM proliferation and cell-cycle arrest and likely contributes towards the pathogenesis of PA/VSD and TOF.

The 30-Year Outcomes of Tetralogy of Fallot According to Native Anatomy and Genetic Conditions.

BACKGROUND: The reported survival of tetralogy of Fallot (TOF) is > 97%. Patients with pulmonary atresia and/or genetic conditions have worse outcomes, but long-term estimates of survival and morbidity for these TOF subgroups are scarce. The objective of this study was to describe the 30-year outcomes of TOF according to native anatomy and the coexistence of genetic conditions. METHODS: The TRIVIA (Tetralogy of Fallot Research for Improvement of Valve Replacement Intervention: A Bridge Across the Knowledge Gap) study is a retrospective population-based cohort including all TOF subjects born from 1980 to 2015 in Québec. We evaluated all-cause mortality by means of Cox proportional hazards regression, and cumulative mean number of cardiovascular interventions and unplanned hospitalisations with the use of marginal means/rates models. We computed 30-year estimates of outcomes according to TOF types, ie, classic TOF (cTOF) and TOF with pulmonary atresia (TOF-PA), and the presence of genetic conditions. RESULTS: We included 960 subjects. The median follow-up was 17 years (interquartile range, 8-27). Nonsyndromic cTOF subjects had a 30-year survival of 95% and had undergone a mean of 2.8 interventions and 0.5 hospitalisations per subject. In comparison, TOF-PA subjects had a lower 30-year survival of 78% and underwent a mean of 8.1 interventions, with 4 times as many hospitalisations. The presence of a genetic condition was associated with lower survival (< 85% for cTOF and < 60% for TOF-PA) but similar numbers of interventions and hospitalisations. CONCLUSIONS: The anatomic types and the presence of genetic conditions strongly influence the long-term outcomes of TOF. We provided robust 30-year estimates for key markers of prognosis that may be used to improve risk stratification and provide more informed counselling to families.

Single-Cell Transcriptomics of Engineered Cardiac Tissues From Patient-Specific Induced Pluripotent Stem Cell-Derived Cardiomyocytes Reveals Abnormal Developmental Trajectory and Intrinsic Contractile Defects in Hypoplastic Right Heart Syndrome.

Background To understand the intrinsic cardiac developmental and functional abnormalities in pulmonary atresia with intact ventricular septum (PAIVS) free from effects secondary to anatomic defects, we performed and compared single-cell transcriptomic and phenotypic analyses of patient- and healthy subject-derived human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and engineered tissue models. Methods and Results We derived hiPSC lines from 3 patients with PAIVS and 3 healthy subjects and differentiated them into hiPSC-CMs, which were then bioengineered into the human cardiac anisotropic sheet and human cardiac tissue strip custom-designed for electrophysiological and contractile assessments, respectively. Single-cell RNA sequencing (scRNA-seq) of hiPSC-CMs, human cardiac anisotropic sheet, and human cardiac tissue strip was performed to examine the transcriptomic basis for any phenotypic abnormalities using pseudotime and differential expression analyses. Through pseudotime analysis, we demonstrated that bioengineered tissue constructs provide pro-maturational cues to hiPSC-CMs, although the maturation and development were attenuated in PAIVS hiPSC-CMs. Furthermore, reduced contractility and prolonged contractile kinetics were observed with PAIVS human cardiac tissue strips. Consistently, single-cell RNA sequencing of PAIVS human cardiac tissue strips and hiPSC-CMs exhibited diminished expression of cardiac contractile apparatus genes. By contrast, electrophysiological aberrancies were absent in PAIVS human cardiac anisotropic sheets. Conclusions Our findings were the first to reveal intrinsic abnormalities of cardiomyocyte development and function in PAIVS free from secondary effects. We conclude that hiPSC-derived engineered tissues offer a unique method for studying primary cardiac abnormalities and uncovering pathogenic mechanisms that underlie sporadic congenital heart diseases.

Pulmonary ductal coarctation and left pulmonary artery interruption; pathology and role of neural crest and second heart field during development.

OBJECTIVES: In congenital heart malformations with pulmonary stenosis to atresia an abnormal lateral ductus arteriosus to left pulmonary artery connection can lead to a localised narrowing (pulmonary ductal coarctation) or even interruption We investigated embryonic remodelling and pathogenesis of this area. MATERIAL AND METHODS: Normal development was studied in WntCre reporter mice (E10.0-12.5) for neural crest cells and Nkx2.5 immunostaining for second heart field cells. Data were compared to stage matched human embryos and a VEGF120/120 mutant mouse strain developing pulmonary atresia. RESULTS: Normal mouse and human embryos showed that the mid-pharyngeal endothelial plexus, connected side-ways to the 6th pharyngeal arch artery. The ventral segment formed the proximal pulmonary artery. The dorsal segment (future DA) was solely surrounded by neural crest cells. The ventral segment had a dual outer lining with neural crest and second heart field cells, while the distal pulmonary artery was covered by none of these cells. The asymmetric contribution of second heart field to the future pulmonary trunk on the left side of the aortic sac (so-called pulmonary push) was evident. The ventral segment became incorporated into the pulmonary trunk leading to a separate connection of the left and right pulmonary arteries. The VEGF120/120 embryos showed a stunted pulmonary push and a variety of vascular anomalies. SUMMARY: Side-way connection of the DA to the left pulmonary artery is a congenital anomaly. The primary problem is a stunted development of the pulmonary push leading to pulmonary stenosis/atresia and a subsequent lack of proper incorporation of the ventral segment into the aortic sac. Clinically, the aberrant smooth muscle tissue of the ductus arteriosus should be addressed to prohibit development of severe pulmonary ductal coarctation or even interruption of the left pulmonary artery.

A rare mosaic 22q11.2 microdeletion identified in a Chinese family with recurrent fetal conotruncal defects.

BACKGROUND: 22q11 deletion syndrome (22qDS) is caused by deletion of chromosome region 22q11.2. However, mosaic cases with 22q11.2 deletion syndrome (22q11.2DS) are rarely reported. METHODS: Chromosomal microarray analysis (CMA) and fluorescence in situ hybridization fluorescence in situ hybridization (FISH) were performed to analyze the copy number alterations. Clinical examinations related to 22q11.2DS were performed on the carrier in this family. RESULTS: A healthy female in a Chinese family with a history of two pregnancies with conotruncal defects, one with pulmonary atresia (PA) and another with Tetralogy of Fallot (TOF) was recruited in this study. CMA revealed that the fetus with TOF has a microdeletion on the 22q11.2 locus, and his mother was further confirmed a somatic mosaicism of 22q11.2 microdeletion by interphase FISH. Somatic mosaic 22q11.2 deletion in the mother was validated in the metaphase lymphocytes. Clinical examinations related to 22q11.2DS showed that the mother had hypocalcemia and low percentages of CD4 + T helper cells. The family history of recurrent fetal conotruncal defects and genetic results demonstrated the inherited possibility of maternal germline mosaicism of the 22q11.2 microdeletion. CONCLUSION: Our report was the first case in a Chinese family to present that a somatic and suspected gonadal mosaicism of the 22q11.2 microdeletion in female causes recurrent fetal conotruncal defects.

MR imaging of subaortic and retroesophageal anomalous courses of the left brachiocephalic vein in the fetus.

The purpose of this study was to report fetal cases of subaortic and retroesophageal anomalous courses of the left brachiocephalic vein (LBCV) evaluated by fetal cardiac magnetic resonance imaging (MRI). A retrospective review of 7282 fetal cardiac MRI from June 2006 to March 2017, nine cases of anomalous courses of the LBCV were correctly diagnosed by fetal cardiac MRI, one case of abnormal subaortic left brachiocephalic vein (ASLBV) missed by fetal MRI was identified postnatally during further imaging of the TOF. The diagnosis was confirmed postnatally by cardiac CT/MRI. An ASLBV was found in 8 cases, a retroesophageal LBCV was found in 2 additional cases with right aortic arch and aberrant left subclavian artery. 3 of 8 ASLBV cases were with a right aortic arch, 4 ASLBV cases had additional cardiovascular anomalies with one case isolated. 7 of 8 ASLBV and 2 retroesophageal LBCV were correctly diagnosed by fetal cardiac MRI; however fetal cardiac MRI missed 2 cases of associated pulmonary atresia (PA). Prenatal echocardiography (echo) correctly diagnosed five ASLBV and one retroesophageal LBCV as well as associated intracardiac anomalies. Fetal cardiac MRI can be a useful adjunct in the identification of subaortic and retroesophageal anomalous courses of the LBCV prenatally.

Aortopulmonary window with pumonary atresia with ventricular septal defect with D-transposition of great arteries: extremely rare anomaly.

Aortopulmonary window (APW) is rare a congenital heart disease accounting for 0.1%-0.2% of all congenital heart defects. The 35% of the APW has been associated with wide variety of other structural heart diseases such as ventricular septal defect, persistent ductus arteriosus, arch anomalies and coronary artery anomalies. To the best of our knowledge, only six cases of APW with pulmonary atresia with ventricular septal defect has been described in the literature. It resembles the type 1 truncus arteriosus, and differentiation from this condition is important prior to surgical correction. We present a case of 14-year-old girl child; she was diagnosed with APW with pulmonary atresia with ventricular septal defect and D transposition of great arteries with the help of echocardiography, cardiac catheterisation and cardiac CT.

Anomalous Left Coronary Artery From Pulmonary Artery in a Baby With Pulmonary Atresia, Intact Ventricular Septum.

A baby with pulmonary atresia with intact ventricular septum and hypoplastic right ventricle, with suspected right ventricle to coronary communications, was operated on for placing an aortopulmonary shunt. Postoperatively, the baby deteriorated with features of myocardial ischemia. Postmortem examination revealed anomalous origin of left coronary artery from pulmonary artery that caused significant coronary ischemia on ligation of the ductus arteriosus. Although coronary anomalies, including right ventricle dependent coronary circulation, has been well described, this is the first report of anomalous origin of coronary artery from pulmonary artery in a baby with pulmonary atresia and intact ventricular septum.

Anatomy of the retro-oesophageal major aortopulmonary collateral arteries in patients with pulmonary atresia with ventricular septal defect: results from preoperative CTA.

OBJECTIVES: To assess the frequency and anatomy of retro-oesophageal aortopulmonary collateral arteries (REMs) in patients with pulmonary atresia with ventricular septal defect and major aortopulmonary collateral arteries (PA-VSD-MAPCAs). METHODS: A total of 130 consecutive PA-VSD-MAPCA patients with preoperative CT angiography (CTA) data who underwent cardiac surgery were included. A detailed analysis of MAPCA anatomy was performed using CTA. RESULTS: A REM was identified in 82/130 included patients (63 %). A total of 277 MAPCAs were observed in these 82 patients and were divided into groups based on REM status: REM (n=94) and non-REM (n=183). Compared with non-REMs, REMs originated at a lower level and tended to originate from the lateral side of the aorta (all p<0.01). REMs had a higher probability of suffering stenosis (χ2=9.79, p<0.01), particularly midsegment stenosis (χ2=6.27, p=0.01). REMs were more posterior to the bronchus at the pulmonary hilum than non-REMs (91 % vs. 51 %) (χ2=50.81, p<0.01). CONCLUSIONS: REMs are associated with a lower level, more lateral origin, stenosis and more posterior location with respect to the bronchus at the pulmonary hilum. The unique CTA data obtained in this study showing the anatomy of REMs will be highly useful for surgeons in identifying REMs. KEY POINTS: • Unifocalization is a very important surgical approach for PA-VSD-MAPCA patients. • The anatomical variability of REMs becomes clinically relevant in unifocalization. • CTA provides a non-invasive way to observe the anatomy of REMs. • REMs are associated with lower level, more lateral origin, more midsegment stenosis. • REMs tend to be posterior to the bronchus at the pulmonary hilum.

Fibromuscular Dysplasia of the Coronary Arteries: A Case Report and Review of the Literature.

Fibromuscular dysplasia is a nonatherosclerotic and non-inflammatory vascular disease with primary lesion of renal and internal carotid arteries. We present a neonatal case of fibromuscular dysplasia who died on the second day of life. The newborn suffered from fibromuscular dysplasia of the coronary arteries and a congenital heart defect. The interesting feature of this case was the formation of aneurysms of the coronary arteries with pulmonary atresia. This case demonstrates a casuistically rare form of association between fibromuscular dysplasia of the coronary arteries and pulmonary artery atresia.

Surgical results for pulmonary atresia with intact ventricular septum: a single-centre 15-year experience and medium-term follow-up.

OBJECTIVES: The optimal surgical strategies for pulmonary atresia with intact ventricular septum (PAIVS) are still not well established. This study reviewed our 15-year experience in the management of PAIVS. METHODS: Between July 1999 and June 2014, 170 patients were treated for PAIVS in our heart centre. Based on the morphology of the right ventricle (RV), age and surgical approaches, the patients were divided into two groups: the one-stage surgery group (n = 33) and the staged surgery group (n = 137), in which patients received definitive repair, including biventricular repair, 1.5 ventricular repair and univentricular palliation without or with initial intervention. The median follow-up time was 6.6 years (range: 1-15 years); survival rates, risk factors for death and clinical status after operation were assessed. RESULTS: In the one-stage surgery group, there were three deaths post operation; the estimated 1-, 5- and 15-year survival rates were 97.0, 93.7 and 88.5%, respectively. In the staged surgery group, 23 patients died, including 15 in the waiting period after initial intervention. The estimated 1-, 5- and 15-year survival rates of the staged group were 89.8, 88.2 and 69.1%, without significant difference when compared with the one-stage surgery group (P > 0.05). Independent predictors of mortality were severe RV hypoplasia (P < 0.05) and lower tricuspid valve Z-scores (P < 0.01). At the latest follow-up, most of the patients in both groups had a good clinical status after definitive repair. The re-operation rate was 16.0% (4/25) in the one-stage surgery group compared with 15.4% (6/39) in the staged surgery group. CONCLUSIONS: Both one-stage repair and the staged surgical procedure had acceptable surgical outcomes in this retrospective study. Initial intervention is suitable for neonates or younger patients to promote the growth of the RV, and one-stage definitive repair is a beneficial choice for older patients with PAIVS, in whom the growth potential of the RV is limited.

Pulmonary atresia with intact ventricular septum and hypoplastic right ventricle in an Arabian foal.

Pulmonary atresia with intact ventricular septum, rudimentary tricuspid valve, hypoplastic right ventricle, and right-to-left atrial shunting were identified in a four-day-old, male Arabian foal with clinical signs of cyanotic heart disease. Pulmonary blood flow was apparently derived from a ductus arteriosus. Echocardiographic evaluation revealed the majority of cardiac abnormalities and also findings compatible with right-sided congestive heart failure. Congenital cardiac defects have a high incidence in this breed, and this is the first description of this combination of congenital cardiac defects.

Ventricular fibrogenesis activity assessed by serum levels of procollagen type III N-terminal amino peptide during the staged Fontan procedure.

OBJECTIVE: We tested the hypotheses that volume overload and cyanosis observed in the pre-Fontan single ventricular circulation are associated with increased ventricular fibrogenesis, that the Fontan procedure helps to reduce fibrogenesis, and that persistently increased fibrogenesis in the Fontan ventricle is associated with ventricular diastolic dysfunction. METHODS: Levels of serum amino-terminal procollagen type III, a marker of tissue fibrogenesis, were measured in 172 patients with single ventricle circulation and 149 controls. Patients were divided into 3 groups according to surgical stage: 59 patients after Blalock-Taussig shunt or pulmonary banding, 60 patients after Glenn surgery (Glenn group), and 53 patients after Fontan surgery (Fontan group). RESULTS: Serum amino-terminal procollagen type III levels were significantly higher among the 3 single ventricle groups than among control patients, but decreased with each surgical stage (0.604, 0.176, 0.143, and 0.073 U/mL, for Blalock-Taussig shunt or pulmonary banding, Glenn, Fontan, and controls, respectively). Severity of volume load and cyanosis were independent determinants of increased amino-terminal procollagen type III levels in patients before Fontan surgery, and persistently increased amino-terminal procollagen type III after Fontan surgery was associated with ventricular diastolic stiffening (r = 0.494, P = .009). Data also indicated close associations between amino-terminal procollagen type III levels and activation of the renin-angiotensin-aldosterone system, suggesting potential involvement of this hormonal system in the increased fibrogenesis after Fontan surgery. CONCLUSIONS: These results suggest that serum amino-terminal procollagen type III may provide important diagnostic information on myocardial fibrosis in patients with single ventricle circulation and raise the possibility that ventricular fibrogenesis may be a potential therapeutic target in this population.

Complete Preoperative Evaluation of Pulmonary Atresia with Ventricular Septal Defect with Multi-Detector Computed Tomography.

OBJECTIVE: To compare multi-detector computed tomography (MDCT) with cardiac catheterization and transthoracic echocardiography (TTE) in comprehensive evaluation of the global cardiovascular anatomy in patients with pulmonary atresia with ventricular septal defect (PA-VSD). METHODS: The clinical and imaging data of 116 patients with PA-VSD confirmed by surgery were reviewed. Using findings at surgery as the reference standard, data from MDCT, TTE and catheterization were reviewed for assessment of native pulmonary vasculature and intracardiac defects. RESULTS: MDCT was more accurate than catheterization and TTE in identification of native pulmonary arteries. MDCT is also the most accurate test for delineation of the major aortopulmonary collateral arteries. The inter-modality agreement for evaluation of overriding aorta and VSD were both excellent. In the subgroup with surgical correlation, excellent agreement was found between TTE and surgery, and substantial agreement was also found at MDCT. CONCLUSION: MDCT can correctly delineate the native pulmonary vasculatures and intracardiac defects and may be a reliable method for noninvasive assessment of global cardiovascular abnormalities in patients with PA-VSD.