High-Throughput Genomics Identify Novel FBN1/2 Variants in Severe Neonatal Marfan Syndrome and Congenital Heart Defects.

Fibrillin-1 and fibrillin-2, encoded by FBN1 and FBN2, respectively, play significant roles in elastic fiber assembly, with pathogenic variants causing a diverse group of connective tissue disorders such as Marfan syndrome (MFS) and congenital contractural arachnodactyly (CCD). Different genomic variations may lead to heterogeneous phenotypic features and functional consequences. Recent high-throughput sequencing modalities have allowed detection of novel variants that may guide the care for patients and inform the genetic counseling for their families. We performed clinical phenotyping for two newborn infants with complex congenital heart defects. For genetic investigations, we employed next-generation sequencing strategies including whole-genome Single-Nucleotide Polymorphism (SNP) microarray for infant A with valvular insufficiency, aortic sinus dilatation, hydronephrosis, and dysmorphic features, and Trio whole-exome sequencing (WES) for infant B with dextro-transposition of the great arteries (D-TGA) and both parents. Infant A is a term male with neonatal marfanoid features, left-sided hydronephrosis, and complex congenital heart defects including tricuspid regurgitation, aortic sinus dilatation, patent foramen ovale, patent ductus arteriosus, mitral regurgitation, tricuspid regurgitation, aortic regurgitation, and pulmonary sinus dilatation. He developed severe persistent pulmonary hypertension and worsening acute hypercapnic hypoxemic respiratory failure, and subsequently expired on day of life (DOL) 10 after compassionate extubation. Cytogenomic whole-genome SNP microarray analysis revealed a deletion within the FBN1 gene spanning exons 7-30, which overlapped with the exon deletion hotspot region associated with neonatal Marfan syndrome. Infant B is a term male prenatally diagnosed with isolated D-TGA. He required balloon atrial septostomy on DOL 0 and subsequent atrial switch operation, atrial septal defect repair, and patent ductus arteriosus ligation on DOL 5. Trio-WES revealed compound heterozygous c.518C>T and c.8230T>G variants in the FBN2 gene. Zygosity analysis confirmed each of the variants was inherited from one of the parents who were healthy heterozygous carriers. Since his cardiac repair at birth, he has been growing and developing well without any further hospitalization. Our study highlights novel FBN1/FBN2 variants and signifies the phenotype-genotype association in two infants affected with complex congenital heart defects with and without dysmorphic features. These findings speak to the importance of next-generation high-throughput genomics for novel variant detection and the phenotypic variability associated with FBN1/FBN2 variants, particularly in the neonatal period, which may significantly impact clinical care and family counseling.

A case report of infective endocarditis in a 52-year-old female with unrepaired tricuspid atresia and d-transposition of the great arteries.

Background: d-Transposition of the great arteries (d-TGA) is a congenital cardiac defect that is typically fatal. Those patients who survive without surgical repair and who are rare in number, need adequate intracardiac shunting and will suffer from chronic cyanosis. Here, we present a rare case of an adult with unrepaired cyanotic congenital heart disease (CHD) who developed infective endocarditis (IE) and also our approach to the medical decision-making process in this uncommonly encountered dilemma. Case summary: A 52-year-old female with unrepaired d-TGA with tricuspid atresia, hypoplastic right ventricle, unrestricted atrial septal defect, ventricular septal defect, and sub-valvular as well as valvular pulmonic stenosis with a hypoplastic, bicuspid pulmonary valve presented with abdominal pain and hypoxia and was found to have an acute renal infarct. Transthoracic echocardiogram (TTE) revealed a large mobile mass on the mitral valve. Blood cultures grew Streptococcus mitis-oralis and she was diagnosed with streptococcal native mitral valve IE complicated by a renal embolus. Her large left-sided vegetation and embolic phenomenon favoured surgery. However, a right heart catheterization showed normal intracardiac pressures, likely a result of multi-level obstruction relating to sub-valvular and valvular pulmonary stenosis protecting the pulmonary vasculature from over-circulation and pulmonary hypertension. Cardiac surgery posed a significant risk of destabilizing her delicately balanced haemodynamics. Hence, she was treated with ceftriaxone for 4 weeks. A repeat TTE 8 weeks later showed a resolution of the vegetation. Discussion: A decision for surgery vs. medical treatment for IE in adult patients with compensated CHD should be made following a multi-disciplinary assessment of each patient's unique cardiac haemodynamics and after shared decision-making with the patient.

Symptomatic Myocardial Bridging in D-Transposition of the Great Arteries Post-Arterial Switch.

We present Stanford's experience with patients post-arterial switch operation presenting with chest pain found to have hemodynamically significant myocardial bridging. The evaluation of symptomatic patients post-arterial switch should not only include assessment for coronary ostial patency but also for nonobstructive coronary conditions such as myocardial bridging. (Level of Difficulty: Advanced.).

Clinical deterioration following arterial switch surgery due to extensive aortopulmonary collaterals, unusual condition but worth considering: case report.

BACKGROUND: The occurrence of major aortopulmonary collateral arteries (MAPCAs) is infrequent in patients with D-transposition of great arteries (D-TGA) with intact ventricular septum (IVS). Hemodynamically significant MAPCAs may complicate the postoperative course of these patients after arterial switch operation (ASO). CASE PRESENTATION: We present a rare case of neonatal D-TGA-IVS associated with extensive MAPCAs. After the ASO, the patient developed pulmonary hemorrhage, chest wall edema, and deterioration of lung compliance with the need for high-frequency ventilation (HFV). The patient also had a significant capillary leak with skin edema, high chest tube drainage, and high peritoneal drainage. Cardiac catheterization revealed extensive MAPCAs supplying the whole lung segments. After the catheter closure of most of these MAPCAs, the patient had clinical improvement. CONCLUSIONS: Although the occurrence of MAPCAs with D-TGA-IVS is infrequent, clinicians should suspect their presence in cases with unexplained heart failure, pulmonary hemorrhage, or cardiovascular compromise after ASO. Catheter closure of MAPCAs is feasible with an acceptable short-term outcome.

Leadless Micra pacemaker implantation in patient with previous Senning procedure for dextro-transposition of the great arteries.

Leadless pacemakers have been developed with key advantages over traditional transvenous pacemakers by substantially mitigating the risks of device infection and lead related complications, and providing an alternative pacing strategy in patients with barriers to superior venous access. The Medtronic Micra leadless pacing system is designed for implantation through a femoral venous approach across the tricuspid valve, via Nitinol tine fixation into the trabeculated subpulmonic right ventricle. Patients with surgically corrected dextro-transposition of the great arteries (d-TGA) have an increased risk of pacing requirement. There is limited published experience of implantation of leadless Micra pacemakers in this population, with key challenges relating to trans-baffle access, and deployment of the device into the less trabeculated subpulmonic left ventricle. Here we describe a case report of leadless Micra implantation in a 49 year old male with d-TGA and Senning procedure in childhood, who required pacing for symptomatic sinus node disease, with anatomic barriers to transvenous pacing. Micra implantation was successfully performed following careful consideration of patient anatomy, including the utilisation of 3D modelling to guide the implantation procedure.

Identification and Subsequent Extraction of an Atrial Pacing Lead Inadvertently Positioned Within the Pulmonary Venous Atrium of a Patient With D-Transposition of the Great Arteries.

In a male patient with D-transposition of the great arteries post Mustard repair, we report the inadvertent placement of an atrial pacemaker lead across the baffle into the pulmonary venous atrium managed with extraction and re-implantation.

Longitudinal functional assessment of atrial M-mode in dextro- transposition of the great arteries fetus may help to predict the necessity for urgent neonatal Rashkind procedure.

Six fetal echocardiographic examinations were analyzed and presented with special emphasis on atrial M-mode in one case of fetal isolated dextro- transposition of the great arteries. The only significant changes were seen based on analysis of the new index of foramen ovale (FO) flap movement. Emergency Rashkind procedure on the first day of postnatal life was predicted based on fetal atrial M-mode.

Coronary artery augmentation with the right subclavian artery for single coronary artery variants of dextro transposition of the great arteries treated by an arterial switch operation.

Objective: Single coronary artery variants in dextro transposition of the great arteries increase the technical demands of performing coronary translocations during the arterial switch operation (ASO). Coronary augmentation using the right subclavian artery as an interposition graft is a viable option in certain cases. The aim of this study is to describe this operative technique and review outcomes. Methods: Of 59 patients who underwent an ASO, from July 2015 to May 2021, 6 had single coronary variants in which the right subclavian artery was used as an interposition graft. Mean follow-up was 21.5 months. Results: Patients mean age and weight at the time of surgery were 7.1 ± 3.8 days and 2.84 ± 0.76 kg, respectively. Four patients had the left anterior descending coronary artery and right coronary artery coming from the left sinus and the circumflex coronary artery coming from the right sinus. One patient had a single ostium arising from the left sinus and another patient had a single ostium coming from the right sinus. All patients are alive and free of cardiac symptoms at follow-up. Conclusions: Single coronary artery variants in dextro transposition of the great arteries can pose technical challenges for coronary translocation during ASO. The augmentation of coronary buttons using a segment of the right subclavian artery is an option which should be considered in selective cases.

Functional assessment of atrial M-mode in 3rd trimester in the context of postnatal balloon atrial septostomy in fetuses with simple dextro-transposition of the great arteries.

OBJECTIVE: This study aimed to identify new functional echocardiographic features of fetal foramen ovale (FO) to predict the need of urgent balloon atrial septostomy (BAS) in neonates with simple dextro-transposition of the great arteries (d-TGA). METHOD: Single-center prospective study of fetuses, who had prenatal echocardiographic examination <30 days before delivery and fetal diagnosis of simple d-TGA. The subjects were divided according to the need of BAS within the first 24 h after neonatal birth and before arterial switch operation. We analyzed following parameters: FO diameter, pulmonary venous maximal velocity, new FO flap tracings index analyzed by M-mode echocardiography. RESULTS: Out of 130 fetuses, 12 patients were included. Cutoff value of FO index provided maximum sensitivity (100%) and negative predictive value (100%) and cutoff value of FO index multiplied by FO diameter provided maximum specificity (100%) and positive predictive value (100%) in fetuses with fetal d-TGA in predicting need of urgent BAS. CONCLUSION: FO index could potentially be used to predict postnatal haemodynamic stability in fetuses with simple d-TGA. FO index multiplied by FO diameter could potentially be used to predict prenatally the need of urgent BAS following the birth.

Complex complete transposition of great arteries and partial anomalous pulmonary venous connection with an intact interatrial septum-lessons learnt.

The association of pulmonary venous anomaly and a complex complete transposition of great arteries (d-TGA) is a rarity. Managing a combination of anomalies in a single setting is a surgical challenge. We report a very rare association of d-TGA with ventricular septal defect (VSD) and partial anomalous pulmonary venous connection (PAPVC) of the right pulmonary veins to the right atrium with an intact interatrial septum in a month-old infant. The child underwent a single-stage complete repair. Constant vigilance in the immediate postoperative period and early revision is mandatory for a good outcome.

Right ventricular systolic function and associated anatomic risk factors in fetuses with transposition of the great arteries: Evaluation by velocity vector imaging.

Objectives: The aim of this study was to evaluate right ventricular (RV) systolic function in fetuses with transposition of the great arteries (TGA) using velocity vector imaging (VVI) and to investigate the impact of different factors on RV systolic function in TGA fetuses. Methods: This was a retrospective cross-sectional study of fetuses referred to our tertiary center between 2015 and 2019. Maternal and fetal baseline characteristics and conventional echocardiographic and myocardial deformation indices were collected in fetuses with TGA at 20-28 weeks' gestation, which were compared with normal fetuses with comparable gestational age (GA). RV deformational parameters including global and regional longitudinal peak systolic strain, strain rate, and velocity were measured using off-line speckle tracking analysis. The univariate and multivariate linear regression analyses were established to evaluate the independent risk factors for RV global longitudinal systolic strain (RVGLSs) and strain rate (RVGLSRs). Results: In total, 78 fetuses with TGA [including 49 fetuses with complete transposition of the great arteries (d-TGA) and 29 fetuses with Taussig-Bing anomaly (TBA)] and 49 normal fetuses were included. Compared with normal controls, global and most regional RV longitudinal systolic peak velocity, strain, and strain rate were lower in d-TGA and TBA fetuses (P < 0.05). Compared with normal controls, global and most regional RV longitudinal systolic strain was lower in d-TGA fetuses without pulmonary stenosis (PS) and ventricular septal defect (VSD), while RVGLSs and RVGLSRs were lower in TBA fetuses without PS. The VSD was an independent determinant of RVGLSRs (P = 0.024) in the d-TGA group. Additionally, PS was an independent determinant of RVGLSs and RVGLSRs (P = 0.012, P = 0.027) in the TBA group. Conclusion: Early impairment of RV systolic function has already occurred in TGA fetuses during the 2nd trimester of pregnancy. PS, VSD, and foramen ovale (FO) were independent risk factors for decreased RV function.

Case report: successful emergent transcatheter pulmonary valve replacement within failing pulmonary artery conduit in the setting of cardiogenic shock with extracorporeal membrane oxygenation support.

BACKGROUND: To the best of our knowledge, this is the first reported case of transcatheter pulmonary valve replacement (TPVR) with extracorporeal membrane oxygenation (ECMO) support with successful decannulation as a bridge to recovery in a young adult with complex congenital heart disease. CASE SUMMARY: We describe a 24-year-old male patient with a history of D-transposition of the great arteries with ventricular septal defect status post-Rastelli repair at age three lost to follow-up and presenting with severe biventricular failure, left ventricular thrombus, and critical pulmonary conduit stenosis, deemed non-surgical and non-transplant candidate, who underwent conduit stenting and TPVR in the setting of cardiogenic shock. Upon intubation for general anaesthesia, the patient suffered from ventricular tachycardia arrest requiring cardiopulmonary resuscitation and veno-arterial ECMO. Once stabilized, conduit stenting and TPVR was performed with significant haemodynamic improvement and immediate ECMO decannulation with subsequent biventricular function improvement. DISCUSSION: In critically ill patients with complex congenital heart disease that are neither surgical nor transplant candidates, ECMO support can be used as a means of support during a transcatheter intervention to improve haemodynamics and a bridge to recovery, allowing time for future potential candidacy for surgery or transplantation as indicated. Patients with congenital heart disease need regular follow-up in specialty clinics to prevent the development of such critical illness.

Modified pulmonary artery banding: A novel strategy for balancing pulmonary blood flow with transposed great arteries.

OBJECTIVE: To study the outcomes of a novel modified pulmonary artery banding (mPAB) technique used for staged repair of a subset of patients with complex transposition physiology. METHODS: A total of 13 patients who underwent mPAB during their staged repair (biventricular repair [BVR], n = 6) or palliation (1-1/2 repair, n = 1; univentricular repair [UVR], n = 6) from 2004 to 2020 were studied retrospectively. A restrictive interposition graft was used to reconstruct the main PA between the pulmonary root and the distal pulmonary confluence, functioning as a mPAB. Twelve of the 13 patients (92.3%) underwent a concurrent arterial switch operation (ASO), of which 6 were palliative ASOs for 1-1/2 repair (n = 1) or UVR (n = 5). Patient weight and cardiac anatomy determined the size of interposition graft. RESULTS: The disease spectrum included dextro transposition of the great arteries (d-TGA) with multiple ventricular septal defects (VSDs) (n = 4), Taussig-Bing anomaly (n = 3), d-TGA with VSD and hypoplastic right ventricle (RV) (n = 3), double-inlet left ventricle with l-TGA (n = 2), and congenitally corrected TGA with double-outlet RV (n = 1). The Lecompte procedure was performed in 10 patients. Predischarge echocardiography revealed a band gradient of 61 mm Hg (interquartile range [IQR], 40-90 mm Hg) for BVR/1-1/2 ventricular repair (n = 7) and 49 mm Hg (IQR, 37-61 mm Hg) for UVR (n = 6). Survival was 100% at a median follow-up of 3.7 years (IQR, 2.6-4.0 years). CONCLUSIONS: The mPAB technique is effective and reproducible for staged BVR or UVR for patients with TGA. It effectively regulates pulmonary blood flow, may reduce neopulmonary root distortion, and eliminates complications associated with band migration in standard PAB.

Transplantation after Mustard operation for transposition of the great arteries.

As long-term outcomes of congenital heart diseases improve, the probability of adult patients presenting for heart transplantation for late failure of congenitally corrected heart disease also increases. In patients with dextro-transposition of the great arteries (d-TGA) who were initially treated in the era of Mustard or Senning procedures and before Jatene procedure was introduced, progressive systemic right ventricular failure represents a problem in the very long-term follow-up. We report a rare case of heart transplantation as a third operation 36 years after Mustard procedure in a patient with d-TGA experiencing late failure of the systemic right ventricle.

Heart Transplantation in Mustard Patients Bridged With Continuous Flow Systemic Ventricular Assist Device - A Case Report and Review of Literature.

Thirty four-year-old male with history of D-transposition of the great arteries (D-TGA) who underwent Mustard operation at 14 months of age presented in cardiogenic shock secondary to severe systemic right ventricular failure. Catheterization revealed significantly increased pulmonary pressures. Due to the patient's inotrope dependence and prohibitive pulmonary hypertension, he underwent implantation of a Heart Ware HVAD® for systemic RV support. Within 4 months of continuous flow ventricular assist device (VAD) implantation complete normalization of pulmonary vascular resistance (PVR) was achieved. He ultimately underwent orthotopic heart transplantation with favorable outcomes. This is the second report of complete normalization of PVR following VAD implantation into a systemic RV in <4 months. We conducted a thorough literature review to identify Mustard patients that received systemic RV VAD as a bridge to a successful heart transplantation. In this article, we summarize the outcomes and focus on pulmonary hypertension reversibility following VAD implant.

Double-root inversion for complex malposition of the great arteries with tricuspid valve straddling.

Dextro-transposition of the great vessels associated with pulmonary stenosis, double-outlet right ventricle, and straddling of the tricuspid valve is an uncommon condition. Several treatment options are available for this malformation, but most of them are not optimal. For patients with transposition of the great vessels, the gold standard procedure, which is an arterial switch procedure, would usually be performed, whereas for patients with pulmonary stenosis, a Rastelli operation or a Nikaidoh procedure would be proposed. Both of these methods have several advantages and disadvantages. Selected patients can qualify for the double-root rotation procedure, which is limited by the function of the pulmonary and aortic valves, the position of the coronary arteries, and the skill of the surgeon[1]. After a thorough analysis of all the preoperative test results, our patient qualified for a surgical correction of the malformation. Due to preexisting pulmonary regurgitation and severe dilation of the pulmonary root, the patient was not considered a good candidate for the arterial switch operation. Therefore, it was decided that the double-root inversion was the best option. Introduction The double-root inversion gives the patient the possibility of avoiding a reoperation. If the patient were to have the Nikaidoh or the Rastelli procedure, we know that the pulmonary graft would eventually have to be replaced. For this reason, we would like to share our experience with the double-root inversion method.

Gene-environment interactions between air pollution and biotransformation enzymes and risk of birth defects.

Genetic and environmental factors have been observed to influence risks for birth defects, though few studies have investigated gene-environment interactions. Our aim was to examine the interaction terms of gene variants in biotransformation enzyme pathways and air pollution exposures in relation to risk of several structural birth defects. We evaluated the role of ambient air pollutant exposure (nitrogen dioxide [NO2 ], nitrogen oxide, carbon monoxide, particulate matter <10 [PM10 ] and <2.5 [PM2.5 ] microns) during pregnancy and 104 gene variants of biotransformation enzymes from infant bloodspots or buccal cells in a California population-based case-control study in 1997-2006. Cases included cleft lip with or without cleft palate (N = 206), gastroschisis (N = 94), tetralogy of Fallot (N = 69), and dextro-transposition of the great arteries (d-TGA; N = 40) and were compared to 208 nonmalformed controls. Overall, the results were not consistent, though did highlight some associations for further investigation as indicated by Wald chi-square test p value <.1. Increased risk of cleft lip was associated with exposure to high PM10 and two CYP gene variants. High PM2.5 and the variant of SLCO1B1 was associated with increased risk of teratology of Fallot. Higher NO2 and two gene variants, CYP2A6 and SLC01B1, were associated with increased risk of d-TGA. Results for gastroschisis were inconsistent in direction and across pollutants. These exploratory results suggest that some individuals based on their genetic background may be more susceptible to the adverse effects of air pollution.

Impact of ductus arteriosus constriction and restrictive foramen ovale on global hemodynamics for term fetuses with d-TGA.

The ductus arteriosus (DA) constriction and restrictive foramen ovale (FO) are known as the leading cause of compromise and death of fetuses with dextro-transposition of the great arteries (d-TGA). Although the d-TGA fetal hemodynamics is of great importance in making diagnosis and management of the congenital heart defect, it remains poorly understood, particularly in terms of abnormal DA and FO. In this study, we developed a closed-loop 0-1D multiscale model of the fetal cardiovascular system (CVS) specified for the d-TGA circulation and conducted a systematic study of the impact of the DA constriction and restrictive FO on fetal hemodynamics. We found that the DA constriction led to a pronounced increase in the pulmonary artery pressure, pulmonary and mitral valve (PV and MV) regurgitation as well as left heart volume; the restrictive FO was responsible for reducing MV E/A ratio, ie, the ratio of peak early filling and late diastolic filling velocities, and PV peak systolic flow (PSV) but could increase both aortic valve (AV) PSV and aortic isthmus systolic index (ISI). Moreover, the amount of blood flowing through the DA was observed equivalent to that through the FO; the influence of DA constriction on the cerebral and placental perfusions are larger than that of the FO. Our results demonstrate that the proposed fetal cardiovascular model may be a useful tool for studying the underlying mechanisms associated with d-TGA fetal circulation and providing insights into its complex physiology and pathology.

Arterial-level repair of transposition of great arteries without coronary artery transfer.

Hypoplastic ascending aorta and interrupted aortic arch (IAA) are rarely associated with dextro-transposition of the great arteries (D-TGA). Severe hypoplastic ascending aorta may preclude coronary artery transfer making arterial switch operation problematic. We report a case of D-TGA with a large subpulmonic ventricular septal defect, IAA, and hypoplastic ascending aorta that underwent successful biventricular surgical repair without coronary artery transfer.