Common deletion variants causing protocadherin-α deficiency contribute to the complex genetics of BAV and left-sided congenital heart disease.

Bicuspid aortic valve (BAV) with ~1%-2% prevalence is the most common congenital heart defect (CHD). It frequently results in valve disease and aorta dilation and is a major cause of adult cardiac surgery. BAV is genetically linked to rare left-heart obstructions (left ventricular outflow tract obstructions [LVOTOs]), including hypoplastic left heart syndrome (HLHS) and coarctation of the aorta (CoA). Mouse and human studies indicate LVOTO is genetically heterogeneous with a complex genetic etiology. Homozygous mutation in the Pcdha protocadherin gene cluster in mice can cause BAV, and also HLHS and other LVOTO phenotypes when accompanied by a second mutation. Here we show two common deletion copy number variants (delCNVs) within the PCDHA gene cluster are associated with LVOTO. Analysis of 1,218 white individuals with LVOTO versus 463 disease-free local control individuals yielded odds ratios (ORs) at 1.47 (95% confidence interval [CI], 1.13-1.92; p = 4.2 × 10-3) for LVOTO, 1.47 (95% CI, 1.10-1.97; p = 0.01) for BAV, 6.13 (95% CI, 2.75-13.7; p = 9.7 × 10-6) for CoA, and 1.49 (95% CI, 1.07-2.08; p = 0.019) for HLHS. Increased OR was observed for all LVOTO phenotypes in homozygous or compound heterozygous PCDHA delCNV genotype comparison versus wild type. Analysis of an independent white cohort (381 affected individuals, 1,352 control individuals) replicated the PCDHA delCNV association with LVOTO. Generalizability of these findings is suggested by similar observations in Black and Chinese individuals with LVOTO. Analysis of Pcdha mutant mice showed reduced PCDHA expression at regions of cell-cell contact in aortic smooth muscle and cushion mesenchyme, suggesting potential mechanisms for BAV pathogenesis and aortopathy. Together, these findings indicate common variants causing PCDHA deficiency play a significant role in the genetic etiology of common and rare LVOTO-CHD.

Identification of patient variables that are associated with ventricular end-diastolic pressure before the bidirectional Glenn operation.

INTRODUCTION: Systemic ventricular end-diastolic pressure is important in patients with single ventricle heart disease. Predictors of an elevated systemic ventricular end-diastolic pressure prior to bidirectional Glenn operation have been incompletely identified. METHODS: All patients who underwent bidirectional Glenn operation operation at our centre between January 2007 and March 2017 were retrospectively identified and patient variables were extracted. For patients who had undergone Fontan operation at the time of this study, post-Fontan patient variables were also extracted. RESULTS: One-hundred patients were included with a median age at pre-bidirectional Glenn operation catheterisation of 4.5 months. In total, 71 (71%) patients had a systemic right ventricle. At the pre-bidirectional Glenn operation catheterisation, the mean systemic ventricular end-diastolic pressure was higher amongst those with systemic right ventricle compared to left ventricle (9.1 mmHg ± 2.1 versus 7.7 ± 2.7 mmHg, p < 0.01). On univariate analysis, pre-bidirectional Glenn operation systemic ventricular end-diastolic pressure was positively associated with the presence of a systemic right ventricle (p < 0.01), history of recoarctation (p = 0.03), history of Norwood operation (p = 0.04), and ventricular systolic pressure (p < 0.01). On multivariate analysis, systemic ventricular end-diastolic pressure was positively associated with the presence of a systemic right ventricle (p < 0.01) and ventricular systolic pressure (p < 0.01). Amongst those who had undergone Fontan operation at the time of study (n = 49), those with a higher pre-bidirectional Glenn operation systemic ventricular end-diastolic pressure were more likely to have experienced death, transplantation, or listed for transplantation (p = 0.02) and more likely to have had heart failure symptoms (p = 0.04) at a mean time from Fontan of 5.2 years ± 1.3. CONCLUSIONS: In patients undergoing bidirectional Glenn operation operation, the volume-loaded, pre-bidirectional Glenn operation state may expose diastolic dysfunction that has prognostic value.

A Novel Case of Marfan Syndrome in an Infant With Hypoplastic Left Heart Syndrome.

This report describes a case of hypoplastic left heart syndrome (HLHS) and Marfan syndrome presenting in conjunction, and highlights how a connective tissue disorder may alter medical and surgical management of newborns with HLHS.

Self-reported functional health status following interrupted aortic arch repair: A Congenital Heart Surgeons' Society Study.

OBJECTIVES: Improved survival after congenital heart surgery has led to interest in functional health status. We sought to identify factors associated with self-reported functional health status in adolescents and young adults with repaired interrupted aortic arch. METHODS: Follow-up of survivors (aged 13-24 years) from a 1987 to 1997 inception cohort of neonates included completion of functional health status questionnaires (Child Health Questionnaire-CF87 [age <18 years, n = 51] or the Short Form [SF]-36 [age ≥18 years, n = 66]) and another about 22q11 deletion syndrome (22q11DS) features (n = 141). Factors associated with functional health status domains were determined using multivariable linear regression analysis. RESULTS: Domain scores of respondents were significantly greater than norms in 2 of 9 Child Health Questionnaire-CF87 and 4 of 10 SF-36 domains and only lower in the physical functioning domain of the SF-36. Factors most commonly associated with lower scores included those suggestive of 22q11DS (low calcium levels, recurrent childhood infections, genetic testing/diagnosis, abnormal facial features, hearing deficits), the presence of self-reported behavioral and mental health problems, and a greater number of procedures. Factors explained between 10% and 70% of domain score variability (R2 = 0.10-0.70, adj-R2 = 0.09-0.66). Of note, morphology and repair type had a minor contribution. CONCLUSIONS: Morbidities associated with 22q11DS, psychosocial issues, and recurrent medical issues affect functional health status more than initial morphology and repair in this population. Nonetheless, these patients largely perceive themselves as better than their peers. This demonstrates the chronic nature of interrupted aortic arch and suggests the need for strategies to decrease reinterventions and for evaluation of mental health and genetic issues to manage associated deteriorations.

Successful Salvage of an Extracardiac Fontan in the Setting of Purulent Mediastinitis using Antibiotic-Impregnated Beads.

Post-cardiotomy mediastinitis is an especially serious complication after the implantation of prosthetic vascular grafts. Standard of care is irrigation, debridement, and removal of all prosthetic material present in the surgical field. The use of antibiotic impregnated beads at the site of infection has been reported in the salvage of vascular grafts in the adult population. We present the case of a 3-year-old child with hypoplastic left heart syndrome who developed mediastinitis following the Fontan operation. In a nontraditional approach, the Fontan conduit, which was surrounded by gross purulence, was successfully salvaged with the adjunctive use of vancomycin-impregnated beads.

Vitamin D Status After Cardiopulmonary Bypass in Children With Congenital Heart Disease.

Deficiency in 25-hydroxyvitamin D (25OHD) is associated with increased morbidity and mortality in the critically ill. Children who underwent surgery for congenital heart disease under cardiopulmonary bypass (CPB) are typically deficient in 25OHD. It is unclear whether this deficiency is due to CPB. We hypothesized that CPB reduces the levels of 25OHD in children with congenital heart disease. We conducted a prospective observational study on children aged 2 months to 17 years who underwent CPB. Serum was collected at 3 time points: immediately before, immediately after surgery, and 24 hours after surgery. 25-Hydroxyvitamin D, 1,25-dihydroxyvitamin D, 1,25(OH)2D, vitamin D binding protein, and albumin levels were measured. Levels were compared using repeated measures analysis of variance. We enrolled 20 patients, 40% were deficient in 25OHD with levels <20 ng/mL prior to surgery. Mean (±standard deviation) of 25OHD at the 3 time points was 21.3 ± 8 ng/mL, 19 ± 5.8 ng/mL, and 19.5 ± 6.6 ng/mL, respectively ( P = .02). The decrease in 25OHD was observed primarily in children with sufficient levels of 25OHD, with mean levels at the 3 time points: 26.8 ± 4.2 ng/mL, 21.5 ± 5.7 ng/mL, and 23.0 ± 4.9 ng/mL, respectively ( P < .001). Calculated means of free fraction of 25OHD at the 3 time points were 6.2 ± 2.8 pg/mL, 5.8 ± 2.2 pg/mL, and 5.5 ± 2.4 pg/mL, respectively, ( P = .04). Mean levels of 1,25(OH)2D were 63.7 ± 34.9 ng/mL, 53.2 ± 30.6 ng/mL, and 67.7 ± 23.5 ng/mL ( P = .04). Vitamin D binding protein and albumin levels did not significantly change. Cardiopulmonary bypass decreases 25OHD by reducing the free fraction. Current investigations are geared to establish whether vitamin D deficiency is associated with outcomes and if treatment is appropriate.

Quality of Life for Historic Cavopulmonary Shunt Survivors.

BACKGROUND: Beginning with Dr William Glenn in 1958, 90 patients with congenital heart lesions underwent cavopulmonary (Glenn) shunts over a 30-year period. In 2015, the follow-up data on this original cohort were reported. The study focuses on the current quality of life of this cohort. METHODS: Of the original 91 cavopulmonary shunt survivors, 14 (ages: 26-59; average length of postsurgical follow-up: 38.4 years) completed the Rand 36-Item Short-Form Health Survey, volume 2 (SF-36v2) quality-of-life survey at clinical office visits, over the phone or via regular mail. Diagnoses included tricuspid atresia (n = 9), double inlet left ventricle (n = 1), d-transposition of great arteries (n = 1), Ebstein's anomaly (n = 1), tetralogy of Fallot (n = 1), and pulmonary atresia with hypoplastic right ventricle (n = 1). Norm-based comparison of cavopulmonary shunt survivors to the general population was performed using a one-sample t test. RESULTS: The 36-question health survey, SF-36v2, provided physical and mental health summary measures standardized to achieve a mean of 50. The 14 survivors' physical composite score was 47.18 (standard deviation [SD]: 8.24; P = .22) and mental composite score was 52.71 (SD: 5.64; P = .095). CONCLUSION: The cavopulmonary shunt is now a widely used surgical palliation for single-ventricle patients and can be associated with physical and mental health outcomes similar to the general US population. Cavopulmonary shunt survivors' SF-36v2 survey results do not demonstrate a statistically significant difference from the general US population in physical or mental health measures. The results of this study contribute to the discussion of quality of life for patients with congenital heart disease by following up with the oldest known survivors.

Early Extubation After Repair of Tetralogy of Fallot and the Fontan Procedure: An Analysis of The Society of Thoracic Surgeons Congenital Heart Surgery Database.

BACKGROUND: There is increasing interest in reducing the duration of mechanical ventilation after pediatric cardiac operations. However, the contemporary use of an early extubation strategy and its effect on clinical outcomes is poorly understood. METHODS: Data from The Society of Thoracic Surgeons Congenital Heart Surgery Database (2010 to 2013) were analyzed to determine the association of early extubation with postoperative length of stay (PLOS). Two operations were analyzed: complete repair of tetralogy of Fallot (TOF) in patients older than 45 days and the Fontan procedure. Centers were stratified into tertiles by frequency of early extubation, defined as less than 6 hours after leaving the operating room. Patients extubated after 48 hours were excluded. RESULTS: Among 92 centers, early extubation was performed in 31.5% (478 of 1,519) of children undergoing TOF repair and in 69.8% (1,153 of 1,653) of those undergoing the Fontan procedure. Early extubation after TOF repair was associated with heavier weight at operation (p < 0.001) and fewer preoperative risk factors (p = 0.016). After adjustment for covariates, average PLOS after TOF repair was shorter for centers in the highest tertile of early extubation rate than for the lowest tertile centers, which have low early extubation rate (p = 0.04). No association was found between center early extubation rate and PLOS for Fontan procedures (p = 0.08). CONCLUSIONS: Early extubation is common after repair of TOF and the Fontan procedure. A high institutional rate of early extubation after TOF repair is associated with shorter PLOS. Further analysis is needed to understand what effect early extubation might have on other meaningful measures such as resource use.

Half a Century's Experience With the Superior Cavopulmonary (Classic Glenn) Shunt.

BACKGROUND: Five decades after its introduction, the Glenn shunt remains an integral step for patients undergoing single-ventricle palliation. We performed a longitudinal follow-up of the original cohort of patients who underwent Glenn shunt. METHODS: We performed a retrospective study of the original cohort of patients who underwent Glenn shunt at Yale between 1958 and 1988. Electronic medical records and chart review up to current era were used to collect data. RESULTS: Ninety-one patients underwent a Glenn shunt at an average age of 6.6 ± 2.5 years, of which 89 were classic Glenn shunts. Median overall survival was 43 years (range, 2 to 56; 95% confidence interval [CI], 39.5 to 46.5) while median survival from the Glenn shunt was 31.4 years (range, 0 to 45; 95% CI, 23.9 to 38.9). Forty-six patients died, 7 in the early postoperative period and 39 late deaths. Twenty-six patients were lost to follow-up. Nineteen patients remain alive with active clinical follow-up, 6 of whom still live with their classic Glenn shunt without conversion to bidirectional Glenn. Twenty-six patients (31%) developed pulmonary arteriovenous fistula with 11 patients (42%) requiring coil embolization. No patient developed thrombosis of the Glenn shunt. There were a total of 28 patients who developed arrhythmias, mostly in the tricuspid atresia group (n = 16), with the majority being atrial tachyarrhythmias (48%). Sixteen patients required permanent pacemaker placement for sinus node dysfunction. CONCLUSIONS: The Glenn shunt continues to provide excellent staged palliation in single-ventricle patients and a bridge to two-ventricle repair. Arrhythmias and pulmonary arteriovenous fistulas were common among single-ventricle cohort. Quality-of-life evaluation of the surviving patients would be an important outcome measure for future investigation.

Anomalous Origins of Coronary Arteries From the Pulmonary Artery: A Comprehensive Review of Literature and Surgical Options.

Anomalous origins of coronary arteries from the pulmonary artery are rare malformations in which the coronary arteries originate from pulmonary artery sinuses or branches. The consequences are variable although, in most cases, these anomalies lead to severe coronary hypoperfusion and ventricular dysfunction. Surgical correction is indicated once the diagnosis is established due to high early mortality associated with the disease. In nearly all cases, the anomalous artery can be excised from its pulmonary origin, mobilized, and reimplanted directly into the ascending aorta using different surgical techniques. In rare circumstances, technical modifications must be used to restore a normal dual coronary perfusion. The emphasis of this article is to provide a collective review of surgical options published in the literature.

Survival and right ventricular performance for matched children after stage-1 Norwood: Modified Blalock-Taussig shunt versus right-ventricle-to-pulmonary-artery conduit.

OBJECTIVE: Early survival advantages after Norwood with right-ventricle-(RV)-to-pulmonary-artery conduit (NW-RVPA) over Norwood-operation with a Blalock-Taussig shunt (NW-BT) are offset by concerns regarding delayed RV dysfunction. We compared trends in survival, RV dysfunction, and tricuspid valve regurgitation (TR) between NW-RVPA and NW-BT for propensity-matched neonates with critical left ventricular outflow tract obstruction (LVOTO). METHODS: In an inception cohort (2005-2014; 21 institutions), 454 neonates with critical LVOTO underwent Norwood stage 1. Propensity-score matching paired 169 NW-RVPA patients with 169 NW-BT patients. End-states were compared between NW-RVPA and NW-BT using competing-risks, multiphase, parametric, hazard analysis. Post-Norwood echocardiogram reports (n = 2993) were used to grade RV dysfunction and TR. Time-related prevalence of ≥moderate RV dysfunction and TR were characterized using nonlinear mixed-model regression, and compared between groups via multiphase, parametric models. RESULTS: Overall 6-year survival was better after NW-RVPA (70%) versus NW-BT (55%; P < .001). Additionally, transplant-free survival during this time was better after NW-RVPA (64%) versus NW-BT (53%; P = .004). Overall prevalence of ≥moderate RV dysfunction reached 11% within 3 months post-Norwood. During this time, RV dysfunction after NW-BT was 16% versus 6% after NW-RVPA (P = .02), and coincided temporally with an increased early hazard for death. For survivors, late RV dysfunction was <5% and was not different between groups (P = .36). Overall prevalence of ≥moderate TR reached 13% at 2 years post-Norwood and was increased after NW-BT (16%) versus NW-RVPA (11%; P = .003). Late TR was similar between groups. CONCLUSIONS: Among propensity-score-matched neonates with critical LVOTO, NW-RVPA offers superior 6-year survival with no greater prevalence of RV dysfunction or TR than conventional NW-BT operations.

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.

Persistent Pulmonary Hypertension in a Neonate With Transposition of Great Arteries and Intact Ventricular Septum: A Case Report and Review of the Literature.

Transposition of the great arteries (TGA) with intact ventricular septum (IVS) has very favorable short- and long-term surgical outcome. Although rare, when associated with persistent pulmonary hypertension (PPH), it exhibits significant mortality risk and management challenges. We report the case of a neonate with TGA with IVS and PPH who underwent successful early surgical repair with emphasis on clinical management and review of the literature.

Repair of anomalous aortic origin of a coronary artery in 113 patients: a Congenital Heart Surgeons' Society report.

BACKGROUND: Anomalous aortic origin of a coronary artery (AAOCA) encompasses a wide morphologic spectrum, which has impeded consensus regarding indications for the diverse repair strategies. We constructed a profile of current surgical techniques and explore their application to morphologic variants. METHODS: Patients<30 years old (n=113) with isolated AAOCA who underwent operations at 29 Congenital Heart Surgeons Society (CHSS) institutions from 1998 to 2012 were identified from the CHSS AAOCA Registry. Operative findings were related to surgical techniques at index repairs by cross-tabulation. RESULTS: Anomalous origin of the left main or left anterior descending coronary artery was present in 33 (29%) patients and of the right coronary artery in 78 (69%) patients; 2 arteries originated directly above the commissure between the left and right sinuses. There were 101 (89%) interarterial and intramural (IA/IM) arteries, 10 (9%) were interarterial but not intramural (IA/NIM) and 2 (2%) were neither interarterial nor intramural. Intramural arteries were unroofed in 100 (88%) operations, usually with intimal tacking after incision (n=47) or excision (n=25) of the common wall. Coronary reimplantation (n=11), pulmonary artery relocation (n=7; 5 for IA/NIM), simple ostioplasty (without unroofing; n=3), coronary artery bypass grafting (n=2), and ostial window (n=1) were less common. In 37 (33%) operations, a valvar commissure was taken down; 33 were resuspended. CONCLUSION: Current surgical repair of AAOCA is individualized to morphology, particularly the presence of intramural and/or interarterial segments. This report is foundational for future planned CHSS studies that will examine interventional and noninterventional outcomes and ultimately guide management of AAOCA.

The effect of modified ultrafiltration on angiopoietins in pediatric cardiothoracic operations.

BACKGROUND: Cardiopulmonary bypass subjects patients' blood to hemodilution and nonphysiologic conditions, resulting in a systemic inflammatory response. Modified ultrafiltration (MUF) counteracts hemodilution and has also been postulated to improve outcomes by proinflammatory cytokine removal. The objective of this study was to investigate whether the benefits of MUF include the removal of proinflammatory mediators, such as angiopoietin-2 (angpt-2). We hypothesize that some of the clinical benefits of MUF are related to the preferential removal of angpt-2. METHODS: We performed a prospective cohort study in children 18 years old or younger undergoing cardiopulmonary bypass. Serum samples were obtained from each patient preoperatively, after cardiopulmonary bypass, and on intensive care unit admission. A fluid sample from the MUF effluent was also analyzed. Angpt-1, angpt-2, interleukin-8, and interleukin-10 levels were determined by enzyme-linked immunosorbent assay. RESULTS: Thirty-one patients were enrolled. Angpt-1 levels significantly decreased across all time points (p<0.01). Angpt-2 concentrations were significantly elevated at intensive care unit admission when compared with both preoperative and post-cardiopulmonary bypass levels (p<0.01). The angpt-2:1 ratio significantly increased after cardiopulmonary bypass to intensive care unit admission (p<0.01). There was no significant difference between the angpt-2 or angpt-1 percentage of extraction within MUF effluent. Interleukin-8 and interleukin-10 significantly increased from preoperative to intensive care unit admission (both p<0.01). CONCLUSIONS: The results of this study demonstrate that MUF removes both proinflammatory and antiinflammatory mediators equally. This study suggests that the clinical benefits of MUF cannot be attributed to the removal of larger quantities of proinflammatory mediators such as angpt-2 and interleukin-8.

Surgical repair of pulmonary venous stenosis: a word of caution.

BACKGROUND: Pulmonary vein stenosis (PVS), both congenital and acquired, is challenging to treat surgically with uncertain long-term results. We reviewed an 11-year surgical experience in 52 children. METHODS: From 2002 to 2012, 52 children age 0 days to 13 years (mean 1.9 years, median 11.7 months) weighing 2.2 to 32.5 kg (mean 9.3 kg, median 7.6 kg) had surgical relief of PVS. Based on clinical characteristics or complexity, 33 (63%) had a sutureless pericardial well repair and 19 (37%) had a more standard patch repair. There were no significant differences in clinical characteristics between the 2 techniques. Twenty children (38%) had prior anomalous pulmonary vein repair and 8 had primary pulmonary vein stenosis; 26 (50%) had other operations at the time of PVS relief. RESULTS: There were 2 hospital deaths (10.5%) in the "standard" group and 5 (15.2%) in the sutureless group (p>0.99). Despite postoperative evidence of PVS relief by echocardiogram or cardiac cath in all patients, at 5 years, actuarial freedom from PVS recurrence or death in the hospital survivors was 67% in the standard group and 58% in the sutureless group. Most recurrences or deaths occurred within 6 months of operation. Heterotaxy, single ventricle anatomy, bilateral disease, and previous anomalous pulmonary vein repair were not predictors of failure. CONCLUSIONS: Surgical treatment of pulmonary vein stenosis remains a challenging problem with nontrivial early mortality and ongoing risk for recurrence or death regardless of surgical technique employed. Clearly, development of methods for earlier intervention or detection and improved surgical techniques are warranted.