Genome Sequencing is Critical for Forecasting Outcomes following Congenital Cardiac Surgery.

While genome sequencing has transformed medicine by elucidating the genetic underpinnings of both rare and common complex disorders, its utility to predict clinical outcomes remains understudied. Here, we used artificial intelligence (AI) technologies to explore the predictive value of genome sequencing in forecasting clinical outcomes following surgery for congenital heart defects (CHD). We report results for a cohort of 2,253 CHD patients from the Pediatric Cardiac Genomics Consortium with a broad range of complex heart defects, pre- and post-operative clinical variables and exome sequencing. Damaging genotypes in chromatin-modifying and cilia-related genes were associated with an elevated risk of adverse post-operative outcomes, including mortality, cardiac arrest and prolonged mechanical ventilation. The impact of damaging genotypes was further amplified in the context of specific CHD phenotypes, surgical complexity and extra-cardiac anomalies. The absence of a damaging genotype in chromatin-modifying and cilia-related genes was also informative, reducing the risk for adverse postoperative outcomes. Thus, genome sequencing enriches the ability to forecast outcomes following congenital cardiac surgery.

Extremely Long-Term Follow-Up of Dr William Glenn's Original Patient Cohort With Superior Cavopulmonary Anastomosis (1958-1990).

BACKGROUND: Historically, Dr William Glenn performed the first classic superior cavopulmonary anastomosis in a seven-year-old child at Yale in 1958. By 1990, this operation was performed consecutively in over 90 patients. With over 60 years of follow-up, this is the longest survival record of early Glenn patients from the first 30 years. METHODS: We performed a single center, retrospective evaluation of patients undergoing a Glenn operation. A collected list of surviving patients, previously updated in 1988, included demographics, age at procedure, and underlying diagnosis. Follow-up data were obtained in May 2022 using electronic medical records to determine survival, age of survivors, and age of deceased. RESULTS: Ninety-five patients underwent the Glenn operation from 1958 to 1990: 58.9% (n = 56) were male and 41.1% (n = 39) female. Fifteen patients were lost to follow-up, but 12 were alive in 1988. Sixty patients were deceased (68.1%), with an average age of 33.5 ± 18.3(range, 2-78, excluding seven early deaths) years. The oldest patient who passed away was a 78-year-old male with tetralogy of Fallot. Twenty patients remain alive, with an average age of 47.5 (range, 32-66) years. Four patients who are still alive today (20% survivors) are older than 60 years. CONCLUSIONS: Since Dr Glenn's original operation, the technique, timing, and indications have been modified (ie, bidirectional Glenn) to adapt to the current era. By following this initial group of patients, we can approach completion of the survival rates for adult congenital patients who were some of the first pediatric patients to receive this ground-breaking palliative procedure.

Hybrid palliation versus nonhybrid management for a multi-institutional cohort of infants with critical left heart obstruction.

OBJECTIVE: To compare patient characteristics and overall survival for infants with critical left heart obstruction after hybrid palliation (bilateral pulmonary artery banding with or without ductal stenting) versus nonhybrid management (eg, Norwood, primary transplantation, biventricular repair, or transcatheter/surgical aortic valvotomy). METHODS: From 2005 to 2019, 1045 infants in the Congenital Heart Surgeons' Society critical left heart obstruction cohort underwent interventions across 28 institutions. Using a balancing score propensity analysis, 214 infants who underwent hybrid palliation and 831 infants who underwent nonhybrid management were proportionately matched regarding variables significantly associated with mortality and variables noted to significantly differ between groups. Overall survival between the 2 groups was adjusted by applying balancing scores to nonparametric estimates. RESULTS: Compared with the nonhybrid management group, infants who underwent hybrid palliation had lower birth weight, smaller gestational age, and higher prevalence of in-utero interventions, noncardiac comorbidities, preoperative mechanical ventilation, absent interatrial communication, and moderate or severe mitral valve stenosis (all P values < .03). Unadjusted 12-year survival after hybrid palliation and nonhybrid management, was 55% versus 69%, respectively. After matching, 12-year survival after hybrid palliation versus nonhybrid management was 58% versus 63%, respectively (P = .37). Among matched infants born weighing <2.5 kg, 2-year survival after hybrid palliation versus nonhybrid management was 37% versus 51%, respectively (P = .22). CONCLUSIONS: Infants born with critical left heart obstruction who undergo hybrid palliation have more high-risk characteristics and anatomy versus infants who undergo nonhybrid management. Nonetheless, after adjustment, there was no significant difference in 12-year survival after hybrid palliation versus nonhybrid management. Mortality remains high, and hybrid palliation confers no survival advantage, even for lower-birth-weight infants.

Computed Tomographic 3-Dimensional Virtual Dissection Aiding in Diagnosis and Surgical Planning of a Rare Form of Obstructed Supracardiac Total Anomalous Pulmonary Venous Connection With an Unusual Scimitar-Like Arrangement.

We present a case of a newborn with a rare presentation of obstructed supracardiac total anomalous pulmonary venous connection who required emergent cannulation to extracorporeal membrane oxygenation (ECMO). Computed tomographic angiography of the heart was performed and using novel virtual dissection techniques aided in surgical planning and guidance. Computed tomographic angiography can be successfully performed in neonates with complex congenital heart disease on ECMO without adjustment of flows to aid in surgical management and novel virtual dissection techniques aid in complex anatomical delineation and spatial orientation with noncardiac structures. The preoperative imaging in this case allowed for appropriate and detailed presurgical planning and contributed to the excellent outcome of this patient.

Pioneers in congenital cardiac surgery: Dr. William Imon Norwood, Jr, MD, PhD.

"Innovation is not only the fountainhead but the life's blood of our specialty, of surgery, of medicine, of business, or of just about anything that is progressing, evolving, and improving. In the absence of innovation there is stagnation and ultimately there is decay. Cardiac surgery, particularly congenital cardiac surgery, must continue to evolve through innovation."

Standardized Aortic Valve Neocuspidization for Treatment of Aortic Valve Diseases.

BACKGROUND: Aortic valve replacement is the traditional surgical treatment for aortic valve diseases, yet standardized aortic valve neocuspidization (AVNeo) is a promising alternative that is gaining popularity. The purpose of this article is to review the available published literature of AVNeo using glutaraldehyde-treated autologous pericardium, also known as the Ozaki procedure, including indications, outcomes, potential benefits, and modes of failure for the reconstructed valve. METHODS: A comprehensive literature search was performed using keywords related to aortic valve repair, AVNeo, or Ozaki procedure. All articles describing performance of AVNeo were reviewed. RESULTS: Reported early mortality after AVNeo varies from 0% to 5.88%. The largest cohort of patients in the literature includes 850 patients with an inhospital mortality rate of 1.88%. Cumulative incidence of aortic valve reoperation was 4.2% in the largest series. Reoperation was uncommon and mainly due to infective endocarditis or degeneration of the reconstructed valve (most commonly due to aortic valve regurgitation, rather than stenosis). CONCLUSIONS: Aortic valve neocuspidization is a versatile and standardized alternative to aortic valve replacement with a biological prosthesis. Early to midterm outcomes from a number of centers are excellent and demonstrate the safety and durability of the procedure. Long-term outcomes and clinical trial data are necessary to determine which patients benefit the most from this procedure.

Robotic, totally endoscopic atrial septal defect repair.

Atrial septal defect accounts for 10-15% of congenital heart disease cases. Small-diameter atrial septal defects diagnosed during infancy or early adulthood are prone to spontaneous closure, whereas uncorrected, persistent moderate or large atrial septal defects can induce left-to-right shunting, which causes volume overload, heart failure, atrial arrhythmia, and/or pulmonary hypertension starting between the third and fourth decades of life. We describe in detail our technique for totally endoscopic, robotic-assisted atrial septal defect repair.

Sequential Defects in Cardiac Lineage Commitment and Maturation Cause Hypoplastic Left Heart Syndrome.

BACKGROUND: Complex molecular programs in specific cell lineages govern human heart development. Hypoplastic left heart syndrome (HLHS) is the most common and severe manifestation within the spectrum of left ventricular outflow tract obstruction defects occurring in association with ventricular hypoplasia. The pathogenesis of HLHS is unknown, but hemodynamic disturbances are assumed to play a prominent role. METHODS: To identify perturbations in gene programs controlling ventricular muscle lineage development in HLHS, we performed whole-exome sequencing of 87 HLHS parent-offspring trios, nuclear transcriptomics of cardiomyocytes from ventricles of 4 patients with HLHS and 15 controls at different stages of heart development, single cell RNA sequencing, and 3D modeling in induced pluripotent stem cells from 3 patients with HLHS and 3 controls. RESULTS: Gene set enrichment and protein network analyses of damaging de novo mutations and dysregulated genes from ventricles of patients with HLHS suggested alterations in specific gene programs and cellular processes critical during fetal ventricular cardiogenesis, including cell cycle and cardiomyocyte maturation. Single-cell and 3D modeling with induced pluripotent stem cells demonstrated intrinsic defects in the cell cycle/unfolded protein response/autophagy hub resulting in disrupted differentiation of early cardiac progenitor lineages leading to defective cardiomyocyte subtype differentiation/maturation in HLHS. Premature cell cycle exit of ventricular cardiomyocytes from patients with HLHS prevented normal tissue responses to developmental signals for growth, leading to multinucleation/polyploidy, accumulation of DNA damage, and exacerbated apoptosis, all potential drivers of left ventricular hypoplasia in absence of hemodynamic cues. CONCLUSIONS: Our results highlight that despite genetic heterogeneity in HLHS, many mutations converge on sequential cellular processes primarily driving cardiac myogenesis, suggesting novel therapeutic approaches.

Variants of the aortic arch in adult general population and their association with thoracic aortic aneurysm disease.

BACKGROUND: Query a single institution computed tomography (CT) database to assess the prevalence of aortic arch anomalies in general adult population and their potential association with thoracic aortopathies. METHODS: CT chest scan reports of patients aged 50-85 years old performed for any indication at a single health system between 2013 and 2016 were included in the analysis. Characteristics of patients with and without aortic arch anomalies were compared by t test and Fisher exact tests. Logistic regression analysis was performed to assess for independent risk factors of thoracic aortic aneurysm (TAA). RESULTS: Of 21,336 CT scans, 603 (2.8%) described arch anomalies. Bovine arch (n = 354, 58.7%) was the most common diagnosis. Patients with arch anomalies were more likely to be female (p < .001), non-Caucasian(p < .001), and hypertensive (p < .001). Prevalence of TAA in arch anomalies group was 10.8% (n = 65) compared to 4.1% (n = 844) in the nonarch anomaly cohort (p < .001). The highest prevalence of thoracic aneurysm was associated with right-sided arch combined with aberrant left subclavian configuration (33%), followed by bovine arch (13%), and aberrant right subclavian artery (8.2%). On binary logistic regression, arch anomaly (OR = 2.85 [2.16-3.75]), aortic valve pathology (OR 2.93 [2.31-3.73]), male sex (OR 2.38 [2.01-2.80]), and hypertension (OR 1.47 [1.25-1.73]) were significantly associated with increased risk of thoracic aneurysm disease. CONCLUSIONS: Reported prevalence of aortic arch anomalies by CT imaging in the older adult population is approximately 3%, with high association of TAA (OR = 2.85) incidence in this subgroup. This may warrant a more tailored surveillance strategy for aneurysm disease in this subpopulation.

Identifying genetic factors that contribute to the increased risk of congenital heart defects in infants with Down syndrome.

Atrioventricular septal defects (AVSD) are a severe congenital heart defect present in individuals with Down syndrome (DS) at a > 2000-fold increased prevalence compared to the general population. This study aimed to identify risk-associated genes and pathways and to examine a potential polygenic contribution to AVSD in DS. We analyzed a total cohort of 702 individuals with DS with or without AVSD, with genomic data from whole exome sequencing, whole genome sequencing, and/or array-based imputation. We utilized sequence kernel association testing and polygenic risk score (PRS) methods to examine rare and common variants. Our findings suggest that the Notch pathway, particularly NOTCH4, as well as genes involved in the ciliome including CEP290 may play a role in AVSD in DS. These pathways have also been implicated in DS-associated AVSD in prior studies. A polygenic component for AVSD in DS has not been examined previously. Using weights based on the largest genome-wide association study of congenital heart defects available (2594 cases and 5159 controls; all general population samples), we found PRS to be associated with AVSD with odds ratios ranging from 1.2 to 1.3 per standard deviation increase in PRS and corresponding liability r2 values of approximately 1%, suggesting at least a small polygenic contribution to DS-associated AVSD. Future studies with larger sample sizes will improve identification and quantification of genetic contributions to AVSD in DS.

Refining The Society of Thoracic Surgeons Congenital Heart Surgery Database Mortality Risk Model With Enhanced Risk Adjustment for Chromosomal Abnormalities, Syndromes, and Noncardiac Congenital Anatomic Abnormalities.

BACKGROUND: The Society of Thoracic Surgeons Congenital Heart Surgery Database Mortality Risk Model adjusts not only for procedure and age group pairings but also for additional patient factors, including the binary presence or absence of a chromosomal abnormality (CA), syndrome (S), and/or a noncardiac congenital anatomic abnormality (NCAA). This analysis refines case-mix adjustment by adding more granular adjustment for individual conditions (CA, S, and NCAA), consistent with a hypothesis that associated risk of mortality differs between individual conditions. METHODS: CA/S corresponding to the same condition were merged to a single condition code. Odds ratios were estimated for all CA/S. For CA/S associated with at least 10 deaths in neonates and infants and at least 10 deaths in children and adults, odds ratios were estimated for the effect of the CA/S separately in neonates/infants and in children/adults. In addition to these condition/age interactions, condition/age/procedure interactions were explored (eg, effect of Down syndrome was estimated based on age and procedure subgroups, including atrioventricular canal repair and single-ventricle palliation). Bayesian modeling was used to create 5 maximally homogeneous groups of CA/S from 81 candidate CA/S variables. A standard logistic regression model then incorporated indicator variables for the 5 categories of CAs/Ss, 7 unique NCAAs, and all other covariates in the previously published Society of Thoracic Surgeons Congenital Heart Surgery Database Mortality Model. RESULTS: Analysis included 107,062 operations in 100 centers (2010 to 2015). Operative Mortality was 3,629 (3.4%). In the development sample, the C statistics of the original nonaugmented model and the augmented model were 0.872 and 0.875, respectively. CONCLUSIONS: The Society of Thoracic Surgeons Congenital Heart Surgery Database Mortality Risk Model has been augmented by addition of covariates representing individual CAs, Ss, and NCAAs.

Intervention for arch obstruction after the Norwood procedure: Prevalence, associated factors, and practice variability.

OBJECTIVE: Arch obstruction after the Norwood procedure is common and contributes to mortality. We determined the prevalence, associated factors, and practice variability of arch reintervention and assessed whether arch reintervention is associated with mortality. METHODS: From 2005 to 2017, 593 neonates in the Congenital Heart Surgeons' Society Critical Left Heart Obstruction cohort underwent a Norwood procedure. Median follow-up was 3.7 years. Multivariable parametric models, including a modulated renewal analysis, were performed. RESULTS: Of the 593 neonates, 146 (25%) underwent 218 reinterventions for arch obstruction after the Norwood procedure: catheter-based (n = 168) or surgical (n = 50) at a median age of 4.3 months (quartile 1-quartile 3, 2.6-5.7). Interdigitation of the distal aortic anastomosis was protective against arch reintervention. Development of ≥ moderate tricuspid valve regurgitation and right ventricular dysfunction at any point was associated with arch reintervention. Nonsignificant variables for arch reintervention included shunt type and preoperative aortic measurements. Surgical arch reintervention was protective against arch reintervention, but transcatheter reintervention was associated with increased reintervention. Arch reintervention was not associated with increased mortality. There was wide institutional variation in incidence of arch reintervention (range, 0-40 reinterventions per 100 years patient follow-up) and in preintervention gradient (range, 0-64 mm Hg). CONCLUSIONS: Interdigitation of the distal aortic anastomosis during the Norwood procedure decreased the risk of arch reintervention. Surgical arch reintervention is more definitive than transcatheter. Arch reintervention after the Norwood procedure is not associated with increased mortality. Serial surveillance for arch obstruction, integrated with changes in right ventricular function and tricuspid valve regurgitation, is recommended after the Norwood procedure to improve outcomes.

Is a hybrid strategy a lower-risk alternative to stage 1 Norwood operation?

BACKGROUND: For neonates with critical left ventricular outflow tract obstruction (LVOTO), hybrid procedures are an alternative to the Norwood stage 1 procedure. Despite perceived advantages, however, outcomes are not well defined. Therefore, we compared outcomes after stage 1 hybrid and Norwood procedures. METHODS: In a critical LVOTO inception cohort (2005-2014; 20 institutions), a total of 564 neonates underwent stage 1 palliation with the Norwood operation with a modified Blalock-Taussig shunt (NW-BT; n = 232; 41%), Norwood operation with a right ventricle-to-pulmonary artery conduit (NW-RVPA; n = 222; 39%), or a hybrid procedure (n = 110; 20%). Post-stage 1 outcomes were analyzed via competing-risks and parametric hazard analyses and compared among all 564 patients and between patients who underwent propensity-matched hybrid and those who underwent NW-BT/NW-RVPA. RESULTS: By 6 years after the stage 1 operation, 50% ± 3%, 7% ± 2%, and 4% ± 1% of patients transitioned to Fontan, transplantation, and biventricular repair, respectively, whereas 7% ± 2% were alive without transition and 32% ± 2% died. Risk factors for death without transition included procedure type, smaller ascending aorta, aortic valve atresia, and lower birth weight. Risk-adjusted 4-year survival was better after NW-RVPA than after NW-BT or hybrid (76% vs 60% vs 61%; P < .001). Furthermore, for neonates with lower birth weight (<∼2 kg), an interaction between birth weight and hybrid resulted in a trend toward better survival after hybrid compared with NW-BT or NW-RVPA. For propensity-matched neonates between hybrid and NW-BT (88 pairs), 4-year survival was similar (62% vs 57%; P = .58). For propensity-matched neonates between hybrid and NW-RVPA (81 pairs), 4-year survival was better after NW-RVPA (59% vs 75%; P = .008). CONCLUSIONS: For neonates with critical LVOTO undergoing single-ventricle palliation, NW-RVPA was associated with the best overall survival. Hybrid strategies are not a lower-risk alternative to Norwood operations overall; however, the impact of lower birth weight on survival may be mitigated after hybrid procedures compared with Norwood operations.

Role of Barium Swallow in Diagnosing Clinically Significant Anastomotic Leak following Esophagectomy.

BACKGROUND: Barium swallow is performed following esophagectomy to evaluate the anastomosis for detection of leaks and to assess the emptying of the gastric conduit. The aim of this study was to evaluate the reliability of the barium swallow study in diagnosing anastomotic leaks following esophagectomy. METHODS: Patients who underwent esophagectomy from January 2000 to December 2013 at our institution were investigated. Barium swallow was routinely done between days 5-7 to detect a leak. These results were compared to clinically determined leaks (defined by neck wound infection requiring jejunal feeds and or parenteral nutrition) during the postoperative period. The sensitivity and specificity of barium swallow in diagnosing clinically significant anastomotic leaks was determined. RESULTS: A total of 395 esophagectomies were performed (mean age, 62.2 years). The indications for the esophagectomy were as follows: malignancy (n=320), high-grade dysplasia (n=14), perforation (n=27), benign stricture (n=7), achalasia (n=16), and other (n=11). A variety of techniques were used including transhiatal (n=351), McKeown (n=35), and Ivor Lewis (n=9) esophagectomies. Operative mortality was 2.8% (n=11). Three hundred and sixty-eight patients (93%) underwent barium swallow study after esophagectomy. Clinically significant anastomotic leak was identified in 36 patients (9.8%). Barium swallow was able to detect only 13/36 clinically significant leaks. The sensitivity of the swallow in diagnosing a leak was 36% and specificity was 97%. The positive and negative predictive values of barium swallow study in detecting leaks were 59% and 93%, respectively. CONCLUSION: Barium swallow is an insensitive but specific test for detecting leaks at the cervical anastomotic site after esophagectomy.

Surgical management of competing pulmonary blood flow affects survival before Fontan/Kreutzer completion in patients with tricuspid atresia type I.

OBJECTIVES: To determine the association between surgical management of pulmonary blood flow (PBF) at initial and staged procedures with survival to Fontan/Kreutzer operation (Fontan) in patients with tricuspid atresia. METHODS: Infants aged <3 months with tricuspid atresia type I (n = 303) were enrolled from 34 institutions (1999-2013). Among those who underwent surgical intervention (n = 302), initial procedures were: systemic to pulmonary artery shunt (SPS; n = 189; 62%); pulmonary artery banding (PAB; n = 50; 17%); and superior cavopulmonary connection (SCPC; n = 63; 21%). Multiphase parametric-hazard models were used to analyze competing outcomes. RESULTS: Risk-adjusted 6-year survival was lower after SPS (85%; P = .04) versus PAB (93%) or SCPC (93%). Survival after SPS when the main pulmonary artery (MPA) was closed (n = 21) or banded (n = 4) was 60%, versus 93% without MPA intervention (P = .02). After SPS, survival before SCPC was lower with an open ductus arteriosus (n = 7; 76% vs 97%; P = .02). Similarly, after SPS, risk-adjusted survival was similar to that for patients who had an initial PAB or SCPC when MPA intervention was avoided and the ductus arteriosus either closed spontaneously before SPS, or was closed during SPS. For all patients reaching SCPC (n = 277), survival to Fontan was not significantly influenced by whether PBF persisted through the MPA. CONCLUSIONS: Tricuspid atresia patients with SPS represent a high-risk subgroup. Avoiding an open ductus arteriosus and concomitant MPA intervention during SPS may help mitigate the risk associated with SPS. The presence of antegrade PBF through the MPA, at initial and staged operations, did not significantly influence survival to Fontan operation.