The MITRIS RESILIA mitral valve is a safe and effective option for mitral valve replacement in young patients requiring mitral valve replacement.

We report the first successful implantation in the United States of a novel mitral valve (MITRIS RESILIA by Edwards Lifesciences) in a patient with history of mitral valve replacement at a young age. This new bioprosthetic valve offers a unique profile and innovative option for mitral valve replacement in patients who are at risk of left ventricular outflow tract obstruction.

An International Survey Comparing Different Physician Models for Health Care Delivery to Critically Ill Children With Heart Disease.

OBJECTIVES: To explore relationships between the training background of cardiac critical care attending physicians and self-reported perceived strengths and weaknesses in their ability to provide clinical care. DESIGN: Cross-sectional observational survey sent worldwide to ~550 practicing cardiac ICU attending physicians. SETTING: Hospitals providing cardiac critical care. SUBJECTS: Practicing cardiac critical care physicians. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We received responses from 243 ICU attending physicians from 82 centers (14 countries). The primary training background of the respondents included critical care (62%), dual training in critical care and cardiology (16%), cardiology (14%), and other (8%). We received 49 responses from medical directors in nine countries, who reported that the predominant training background for attending physicians who provide cardiac intensive care at their institutions were critical care (58%), dual trained (18%), cardiology (12%), and other (11%). A greater proportion of physicians trained in either critical care or dual-training reported feeling confident managing multiple organ failure, neurologic conditions, brain death, cardiac arrest, and performing procedures like advanced airway placement and inserting chest- and abdominal-drains. In contrast, physicians with cardiology and dual-training reported feeling more confident managing intractable arrhythmias, understanding cardiopulmonary interactions, and interpreting echocardiogram, electrocardiogram, and cardiac catheterization. Overall, only 57% of the respondents felt comfortable based on their current training background to manage patients with complex cardiac issues without collaboration with other specialists. CONCLUSIONS: Our survey demonstrates that intensivists trained in critical care are more comfortable with critical care skills, cardiology-trained intensivists are more comfortable with cardiology skills, and dual-trained physicians are comfortable with both critical care skills and cardiology skills. These findings may help inform future efforts to optimize the educational curriculum and training pathways for future cardiac intensivists. These data may also be used to shape continuing medical education activities for cardiac intensivists who have already completed their training.

Gastrostomy and Tracheostomy After Complete Repair of Tetralogy of Fallot in Children With 22q11.2 Deletion Syndrome.

OBJECTIVES: Caring for a child with gastrostomy and/or tracheostomy can cause measurable parental stress. It is generally known that children with 22q11.2 deletion syndrome are at greater risk of requiring gastrostomy or tracheostomy after heart surgery, although the magnitude of that risk after complete repair of tetralogy of Fallot has not been described. We sought to determine the degree to which 22q11.2 deletion is associated with postoperative gastrostomy and/or tracheostomy after repair of tetralogy of Fallot. DESIGN: Retrospective cohort study. SETTING: Pediatric Health Information System. PATIENTS: Children undergoing complete repair of tetralogy of Fallot (ventricular septal defect closure and relief of right ventricular outflow tract obstruction) from 2003 to 2016. Patients were excluded if they had pulmonary atresia, other congenital heart defects, and/or genetic diagnoses other than 22q11.2 deletion. MEASUREMENTS AND MAIN RESULTS: Two groups were formed on the basis of 22q11.2 deletion status. Outcomes were postoperative tracheostomy and postoperative gastrostomy. Bivariate analysis and Kaplan-Meier analysis at 150 days postoperatively were performed. There were 4,800 patients, of which 317 (7%) had a code for 22q11.2 deletion. There were no significant differences between groups for age at surgery or sex. Patients with 22q11.2 deletion had significantly higher rates of gastrostomy (18% vs 5%; p < 0.001) and higher rates of tracheostomy (7% vs 1%; p < 0.001); there was no difference for mortality. Kaplan-Meier analyses also showed higher rates of gastrostomy (p = 0.024) and tracheostomy (p = 0.037). CONCLUSIONS: The present study establishes rates of postoperative gastrostomy and tracheostomy in children with 22q11.2 deletion after complete repair of tetralogy of Fallot. These data are useful to clinicians for providing families with preoperative counseling.

Trans-apical systemic tricuspid valve-in-ring replacement.

Transcatheter valve replacement offers a safe and effective alternative to traditional surgical techniques in patients with congenital heart disease, especially those at high surgical risk. The most common causes of morbidity and mortality in patients with D-transposition of the great arteries status post Senning or Mustard repair is severe tricuspid valve (TV) regurgitation. Replacement of the systemic TV may be useful in those without severe systemic ventricular dysfunction. We present a case of a patient with D-loop transposition of the great arteries status post Mustard repair and TV ring placement with subsequent severe systemic TV regurgitation, at high surgical risk, who underwent a transcatheter valve replacement via a trans-apical approach using an Edwards Sapien XT valve.

Incidence and outcome of infective endocarditis following percutaneous versus surgical pulmonary valve replacement.

OBJECTIVES: To provide a comparison of the outcome of infective endocarditis (IE) in patients undergoing transcatheter pulmonary valve replacement (TPVR) versus surgical pulmonary valve replacement (SPVR). BACKGROUND: Although TPVR is thought to be associated with a higher risk of IE than SPVR, there is paucity of data to support this. METHODS: Patients who underwent TPVR or SPVR at UCLA between October 2010 and September 2016 were included and retrospectively analyzed. RESULTS: Three hundred forty-two patients underwent PVR at UCLA including 134 SPVR and 208 TPVR. Patients undergoing TPVR were more likely to have had a history of endocarditis than those undergoing SPVR (5.3% vs. 0.7%, P = 0.03) and a right ventricle to pulmonary artery (RV to PA) conduit (37% vs. 17%, P = 0.0001). Two SPVR and seven TPVR patients developed IE with a 4-year freedom from endocarditis of 94.0% in the SPVR versus 84% in the TPVR group (P = 0.13). In patients who underwent TPVR and developed endocarditis, the mean gradient across the RVOT prior to intervention was higher (28.1 ± 4.5 vs. 17.4 ± 0.6 mmHg, P = 0.02) and were more likely to have a conduit (71% vs. 36%, P = 0.049). CONCLUSIONS: In this study, patients undergoing TPVR were not at a higher risk of IE than patients undergoing SPVR. TPVR patients were more likely to have had a prior history of IE and RV-PA conduit. The patients at highest risk were those with stenotic RV to PA conduits who were treated with TPVR.

Heparin-Coated Grafts Reduce Mortality in Pediatric Patients Receiving Systemic-to-Pulmonary Shunts.

We aimed to evaluate the outcomes of systemic-to-pulmonary (SP) shunt procedures utilizing heparin-coated (HC) polytetrafluoroethylene (PTFE) vascular grafts compared to uncoated (non-HC) grafts, in order to observe any benefits in pediatric patients. Our institution switched from using non-HC grafts to HC grafts in March 2011. We conducted a retrospective review of consecutive pediatric patients receiving SP shunts from May 2008 to December 2015. Perioperative variables including baseline characteristics, morbidity, mortality, and blood product utilization were evaluated between the HC and non-HC groups. A total of 142 pediatric patients received SP shunts during the study period: 69 patients received HC shunts and 73 patients received non-HC shunts. The HC group had significantly fewer desaturation or arrest events (P < 0.01), fewer shunt occlusions/thromboses (P < 0.01). There was no statistically significant difference in unplanned reoperations between groups (P = 0.18). The HC group demonstrated significantly lower overall 30-day mortality (P < 0.01), as well as shunt-related mortality (P < 0.01). The HC group had significantly lower postoperative packed red blood cell utilization as compared to the non-HC group (P < 0.01). In this study, pediatric patients receiving HC PTFE grafts in SP shunts demonstrated significantly lower shunt-related mortality. The majority of HC grafts remained patent. These findings suggest that HC grafts used in SP shunt procedures may benefit pediatric patients in terms of efficacy and outcomes.

MRI with ferumoxytol: A single center experience of safety across the age spectrum.

PURPOSE: To summarize our single-center safety experience with the off-label use of ferumoxytol for magnetic resonance imaging (MRI) and to compare the effects of ferumoxytol on monitored physiologic indices in patients under anesthesia with those of gadofosveset trisodium. MATERIALS AND METHODS: Consecutive patients who underwent ferumoxytol-enhanced (FE) MRI exams were included. Adverse events (AEs) were classified according to the Common Terminology Criteria for Adverse Events v4.0. In a subgroup of patients examined under general anesthesia, recording of blood pressure, heart rate, oxygen saturation, and end-tidal CO2 was performed. A comparable group of 23 patients who underwent gadofosveset-enhanced (GE) MRI under anesthesia with similar monitoring was also analyzed. RESULTS: In all, 217 unique patients, ages 3 days to 94 years, underwent FE-MRI. No ferumoxytol-related severe, life-threatening, or fatal AEs occurred acutely or at follow-up. Two patients developed ferumoxytol-related nausea. Between-group (FE- vs. GE-MRI) comparisons showed no statistical difference in heart rate (P = 0.69, 95% confidence interval [CI] 96-113 bpm), mean arterial blood pressure (MAP) (P = 0.74, 95% CI 44-52 mmHg), oxygen saturation (P = 0.76, 95% CI 94-98%), and end-tidal CO2 (P = 0.73, 95% CI 31-37 mmHg). No significant change in MAP (P = 0.12, 95% CI 50-58 mmHg) or heart rate (P = 0.25, 95% CI 91-105 bpm) was noted between slow infusion of ferumoxytol (n = 113) vs. bolus injection (n = 104). CONCLUSION: In our single-center experience, no serious AEs occurred with the diagnostic use of ferumoxytol across a wide spectrum of age, renal function, and indications. Because of the limited sample size, firm conclusions cannot be drawn about the generalizability of our results. Thus, vigilance and monitoring are recommended to mitigate potential rare adverse reactions. LEVEL OF EVIDENCE: 2 J. Magn. Reson. Imaging 2017;45:804-812.

4D MUSIC CMR: value-based imaging of neonates and infants with congenital heart disease.

BACKGROUND: 4D Multiphase Steady State Imaging with Contrast (MUSIC) acquires high-resolution volumetric images of the beating heart during uninterrupted ventilation. We aim to evaluate the diagnostic performance and clinical impact of 4D MUSIC in a cohort of neonates and infants with congenital heart disease (CHD). METHODS: Forty consecutive neonates and infants with CHD (age range 2 days to 2 years, weight 1 to 13 kg) underwent 3.0 T CMR with ferumoxytol enhancement (FE) at a single institution. Independently, two readers graded the diagnostic image quality of intra-cardiac structures and related vascular segments on FE-MUSIC and breath held FE-CMRA images using a four-point scale. Correlation of the CMR findings with surgery and other imaging modalities was performed in all patients. Clinical impact was evaluated in consensus with referring surgeons and cardiologists. One point was given for each of five key outcome measures: 1) change in overall management, 2) change in surgical approach, 3) reduction in the need for diagnostic catheterization, 4) improved assessment of risk-to-benefit for planned intervention and discussion with parents, 5) accurate pre-procedural roadmap. RESULTS: All FE-CMR studies were completed successfully, safely and without adverse events. On a four-point scale, the average FE-MUSIC image quality scores were >3.5 for intra-cardiac structures and >3.0 for coronary arteries. Intra-cardiac morphology and vascular anatomy were well visualized with good interobserver agreement (r = 0.46). Correspondence between the findings on MUSIC, surgery, correlative imaging and autopsy was excellent. The average clinical impact score was 4.2 ± 0.9. In five patients with discordant findings on echo/MUSIC (n = 5) and catheter angiography/MUSIC (n = 1), findings on FE-MUSIC were shown to be accurate at autopsy (n = 1) and surgery (n = 4). The decision to undertake biventricular vs univentricular repair was amended in 2 patients based on FE-MUSIC findings. Plans for surgical approaches which would have involved circulatory arrest were amended in two of 28 surgical cases. In all 28 cases requiring procedural intervention, FE-MUSIC provided accurate dynamic 3D roadmaps and more confident risk-to-benefit assessments for proposed interventions. CONCLUSIONS: FE-MUSIC CMR has high clinical impact by providing accurate, high quality, simple and safe dynamic 3D imaging of cardiac and vascular anatomy in neonates and infants with CHD. The findings influenced patient management in a positive manner.

Efficacy of an Extracellular Matrix in Systemic Loading Conditions in Congenital Heart Surgery.

Extracellular matrices (ECM) are commonly used to repair congenital heart defects; however, there is a lack of literature pertaining to outcomes with ECM use in high-pressure conditions. Between 2011 and 2014, a total of 202 patients underwent congenital heart disease repair using the ECM placed in a systemic pressure condition. The operative sites included: defects in the ventricular septum, mitral valve, aortic valve, ascending aorta, and aortic arch. Patients were followed and evaluated for mortality and reoperations due to loss of ECM integrity. Echocardiograms were evaluated for graft malfunction such as aneurysmal dilation, VSD formation, valve malfunction, or outflow tract obstruction. Patients were followed for an average of 1492 days (Median = 1583). Out of the 202 patients, 7 (3.5%) died due to complications unrelated to ECM, and 10 (5%) underwent reoperations due to complications of ECM integrity. Reoperations were as follows: two of 6 patients receiving aortic leaflet replacement required reoperation for leaflet failure; four of 12 patients receiving mitral valve leaflet repairs required reoperation for leaflet failure; and four of 142 patients with VSD repair required reoperation for residual shunting. The average time to reoperation was 208 days. There were no outflow tract obstructions or aneurysmal dilatations observed. This modern case series suggests that the ECM is efficacious and sustainable under systemic conditions in congenital heart defect repair. However, concerns remain about the use of ECM in aortic valve repair and infant mitral valve repair. Further studies are needed to evaluate long-term ECM integrity.

Association Between Hematologic and Inflammatory Markers and 31 Thrombotic and Hemorrhagic Events in Berlin Heart Excor Patients.

Bleeding and thrombotic events remain a significant cause of morbidity in pediatric patients supported with ventricular assist devices (VADs). The objective of this study is to identify the association between markers of anticoagulation and bleeding and thrombosis events during Berlin Heart ExCor support. A retrospective, single-center analysis of 9 patients supported with the Berlin Heart ExCor was performed. Inflammatory and anticoagulation parameters including C-reactive protein, fibrinogen, partial thromboplastin time (PTT), and platelet count were measured at 48 and 24 h before and after bleeding or thrombosis events. Patients served as their own controls, and the same parameters were measured during a control period where subjects did not experience either event. All patients received the anticoagulation regimen proposed by Berlin Heart. A total of 31 bleeding or thrombotic events were identified and matched to 18 control events. Patient with predominantly thrombotic events tended to weigh less than those with bleeding events (Δ7.7 kg, p < 0.001). PTT levels were higher before and after bleeding (Δ17.36, p = 0.002) and thrombosis (Δ8.75, p < 0.001) events relative to control. Heparin dose decreased after a thrombosis event (Δ-5.67, p = 0.097), and this decrease was significantly different from control (p = 0.032). Non-collinearity between heparin dose and PTT should prompt further inflammatory and hematological investigation. In addition, heavier patients were more prone to bleeding complications. The role of inflammation in the development of thrombus or hemorrhages in the pediatric VAD population needs to be studied further.

Effects of acute kidney injury and chronic hypoxemia on fibroblast growth factor 23 levels in pediatric cardiac surgery patients.

BACKGROUND: Fibroblast growth factor-23 (FGF23) levels are elevated in cardiopulmonary bypass (CPB)-associated acute kidney injury (AKI); however, it is unknown how much of the circulating FGF23 is intact and bioactive. Hypoxia may induce FGF23 production, yet its impact in humans is unknown. Pediatric cardiac surgery patients have both a high incidence of CPB-associated AKI and a high prevalence of chronic hypoxemia. METHODS: We assessed the effects of hypoxemia and CPB-associated AKI on C-terminal FGF23 (cFGF23) and intact FGF23 (iFGF23) levels in 32 pediatric cardiac surgery patients with normal estimated glomerular filtration rate (eGFR). Plasma cFGF23 and iFGF23 were measured preoperatively and serially postoperatively. RESULTS: Despite normal renal and ventricular function, preoperative cFGF23 levels were high and elevated out of proportion to iFGF23 levels. Preoperative oxygen saturation measurements correlated inversely with FGF23 levels. Preoperative cFGF23 and oxygen saturation both predicted postoperative AKI. Postoperatively, cFGF23 and iFGF23 increased by 2 h postreperfusion; iFGF23 then returned to baseline, but cFGF23 remained elevated through 24 h postreperfusion. Group status (AKI vs. non-AKI) modified the effect of time on changes in iFGF23 levels but not cFGF23 levels. CONCLUSIONS: Preoperative cFGF23 may predict CPB-associated kidney dysfunction. Changes over time in cFGF23 and iFGF23 levels post-CPB differ. Chronic hypoxemia may affect FGF23 production in humans.

Berlin Heart EXCOR pediatric ventricular assist device for bridge to heart transplantation in US children.

BACKGROUND: Recent data suggest that the Berlin Heart EXCOR Pediatric ventricular assist device is superior to extracorporeal membrane oxygenation for bridge to heart transplantation. Published data are limited to 1 in 4 children who received the device as part of the US clinical trial. We analyzed outcomes for all US children who received the EXCOR to characterize device outcomes in an unselected cohort and to identify risk factors for mortality to facilitate patient selection. METHODS AND RESULTS: This multicenter, prospective cohort study involved all children implanted with the Berlin Heart EXCOR Pediatric ventricular assist device at 47 centers from May 2007 through December 2010. Multiphase nonproportional hazards modeling was used to identify risk factors for early (<2 months) and late mortality. Of 204 children supported with the EXCOR, the median duration of support was 40 days (range, 1-435 days). Survival at 12 months was 75%, including 64% who reached transplantation, 6% who recovered, and 5% who were alive on the device. Multivariable analysis identified lower weight, biventricular assist device support, and elevated bilirubin as risk factors for early mortality and bilirubin extremes and renal dysfunction as risk factors for late mortality. Neurological dysfunction occurred in 29% and was the leading cause of death. CONCLUSIONS: Use of the Berlin Heart EXCOR has risen dramatically over the past decade. The EXCOR has emerged as a new treatment standard in the United States for pediatric bridge to transplantation. Three-quarters of children survived to transplantation or recovery; an important fraction experienced neurological dysfunction. Smaller patient size, renal dysfunction, hepatic dysfunction, and biventricular assist device use were associated with mortality, whereas extracorporeal membrane oxygenation before implantation and congenital heart disease were not.

Use of bivalirudin for anticoagulation during implantation of total artificial heart.

Heparin-induced thrombocytopenia presents a challenge for anticoagulation techniques during cardiac surgery and ventricular assist device implantation. Bivalirudin is currently recommended for use during cardiopulmonary bypass for patients with heparin-induced thrombocytopenia but requires the use of special techniques to avoid blood stagnation. We report the successful use of bivalirudin during cardiopulmonary bypass for implantation of the Total Artificial Heart with late operative bleeding likely resulting from heavy cell saver use.

Aberrant right subclavian artery: a novel approach and an overview of operative techniques.

An aberrant right subclavian artery (ARSA) is a rare variation of normal anatomy occurring in 0.5% to 1.8% of the population. No current guidelines are available regarding ARSA management, and surgical intervention should be evaluated carefully. Moreover, symptomatic patients with a dominant left arch and aberrant ARSA require a surgical approach from the right side of the chest for ligation and division of the aberrant artery at its origin on the aorta. The ARSA can then be reimplanted onto the right common carotid artery via a supraclavicular incision. The extensive mobilization in the chest allows for easy reimplantation in the supraclavicular region and eliminates reliance on the collateral circulation. Postoperative monitoring is reliable and easy with radial pulse examinations.

Coronary Sinus Ostial Obstruction in Single-Ventricle Congenital Heart Disease: Two Patients With Different Outcomes.

Coronary sinus ostial obstruction is an exceedingly rare anomaly that is particularly important to diagnose in patients with single-ventricle heart disease before surgical palliation. We present 2 cases, an infant and an adult, diagnosed with coronary sinus ostial obstruction, with different clinical outcomes due to timing of diagnosis. (Level of Difficulty: Intermediate.).

Gene-environment regulation of chamber-specific maturation during hypoxemic perinatal circulatory transition.

Chamber-specific and temporally regulated perinatal cardiac growth and maturation is critical for functional adaptation of the heart and may be altered significantly in response to perinatal stress, such as systemic hypoxia (hypoxemia), leading to significant pathology, even mortality. Understanding transcriptome regulation of neonatal heart chambers in response to hypoxemia is necessary to develop chamber-specific therapies for infants with cyanotic congenital heart defects (CHDs). We sought to determine chamber-specific transcriptome programming during hypoxemic perinatal circulatory transition. We performed transcriptome-wide analysis on right ventricle (RV) and left ventricle (LV) of postnatal day 3 (P3) mouse hearts exposed to perinatal hypoxemia. Hypoxemia decreased baseline differences between RV and LV leading to significant attenuation of ventricular patterning (AVP), which involved several molecular pathways, including Wnt signaling suppression and cell cycle induction. Notably, robust changes in RV transcriptome in hypoxemic condition contributed significantly to the AVP. Remarkably, suppression of epithelial mesenchymal transition (EMT) and dysregulation of the TP53 signaling were prominent hallmarks of the AVP genes in neonatal mouse heart. Furthermore, members of the TP53-related gene family were dysregulated in the hypoxemic RVs of neonatal mouse and cyanotic Tetralogy of Fallot hearts. Integrated analysis of chamber-specific transcriptome revealed hypoxemia-specific changes that were more robust in RVs compared with LVs, leading to previously uncharacterized AVP induced by perinatal hypoxemia. Remarkably, reprogramming of EMT process and dysregulation of the TP53 network contributed to transcriptome remodeling of neonatal heart during hypoxemic circulatory transition. These insights may enhance our understanding of hypoxemia-induced pathogenesis in newborn infants with cyanotic CHD phenotypes. KEY MESSAGES: During perinatal circulatory transition, transcriptome programming is a major driving force of cardiac chamber-specific maturation and adaptation to hemodynamic load and external environment. During hypoxemic perinatal transition, transcriptome reprogramming may affect chamber-specific growth and development, particularly in newborns with congenital heart defects (CHDs). Chamber-specific transcriptome changes during hypoxemic perinatal transition are yet to be fully elucidated. Systems-based analysis of hypoxemic neonatal hearts at postnatal day 3 reveals chamber-specific transcriptome signatures during hypoxemic perinatal transition, which involve attenuation of ventricular patterning (AVP) and repression of epithelial mesenchymal transition (EMT). Key regulatory circuits involved in hypoxemia response were identified including suppression of Wnt signaling, induction of cellular proliferation and dysregulation of TP53 network.

Impact of Regional Cerebral Perfusion on Outcomes Among Neonates Undergoing Norwood Operation.

OBJECTIVES: To evaluate the impact of regional cerebral perfusion (RCP) during heart operation on outcomes in neonates undergoing Norwood operation. METHODS: We performed a retrospective cohort study using data from the Single Ventricle Reconstruction trial data set. The adjusted effect of RCP use on each outcome was studied using a penalized logistic regression model with bootstrap validation. RESULTS: Of 549 patients included in the study, 252 patients (45.9%) received RCP during their heart operation. In univariate comparisons, the majority of the baseline characteristics and preoperative risk factors were similar in the RCP and No RCP group. The total cardiopulmonary bypass (CPB) time and the total cross-clamp (CC) time were longer in the RCP group (RCP vs No RCP, median CPB time: 161 minutes vs 109 minutes; median CC time: 63 minutes vs 43 minutes). In adjusted models, the use of RCP was not associated with decreased mortality and/or need for heart transplant at hospital discharge (odds ratio [OR]: 0.73; 95% confidence interval [CI]: 0.43-1.25) or prolonged mechanical ventilation (OR: 1.20, 95% CI: 0.62-2.28) or prolonged hospital length of stay (OR: 1.30, 95% CI: 0.73-2.30). We demonstrated that use of RCP was associated with longer CPB times, increased use of ultrafiltration, and higher probability of open chest after Norwood operation. CONCLUSIONS: This study did not demonstrate any impact of RCP on in-hospital mortality and/or heart transplantation, prolonged mechanical ventilation, and prolonged hospital length of stay among neonates undergoing Norwood operation.

Double whammy: A case of bilateral bicuspid arterial valves in transposition, with a review of the literature.

Bicuspidity of both the semilunar valves is rarely reported. We report the first ever case of bilateral bicuspid semilunar valves in a case of transposition.

Gene-environment regulatory circuits of right ventricular pathology in tetralogy of fallot.

The phenotypic spectrum of congenital heart defects (CHDs) is contributed by both genetic and environmental factors. Their interactions are profoundly heterogeneous but may operate on common pathways as in the case of hypoxia signaling during postnatal heart development in the context of CHDs. Tetralogy of Fallot (TOF) is the most common cyanotic (hypoxemic) CHD. However, how the hypoxic environment contributes to TOF pathogenesis after birth is poorly understood. We performed Genome-wide transcriptome analysis on right ventricle outflow tract (RVOT) specimens from cyanotic and noncyanotic TOF. Co-expression network analysis identified gene modules specifically associated with clinical diagnosis and hypoxemia status in the TOF hearts. In particular, hypoxia-dependent induction of myocyte proliferation is associated with E2F1-mediated cell cycle regulation and repression of the WNT11-RB1 axis. Genes enriched in epithelial mesenchymal transition (EMT), fibrosis, and sarcomere were also repressed in cyanotic TOF patients. Importantly, transcription factor analysis of the hypoxia-regulated modules suggested CREB1 as a putative regulator of hypoxia/WNT11-RB1 circuit. The study provides a high-resolution landscape of transcriptome programming associated with TOF phenotypes and unveiled hypoxia-induced regulatory circuit in cyanotic TOF. Hypoxia-induced cardiomyocyte proliferation involves negative modulation of CREB1 activity upstream of the WNT11-RB1 axis. KEY MESSAGES: Genetic and environmental factors contribute to congenital heart defects (CHDs). How hypoxia contributes to Tetralogy of Fallot (TOF) pathogenesis after birth is unclear. Systems biology-based analysis revealed distinct molecular signature in CHDs. Gene expression modules specifically associated with cyanotic TOF were uncovered. Key regulatory circuits induced by hypoxia in TOF pathogenesis after birth were unveiled.